TITLE OF THE INVENTION

"ADIPOSITY-MODULATING MOLECULES AND USES THEREFOR"

FIELD OF THE INVENTION

[0001] This invention relates generally to methods and agents for modulating adiposity and adiposity-related conditions. More particularly, the present invention relates to the use of inhibitors of phospholipase A ₂ , and more particularly phospholipase A ₂ Group Ila (PLA2G2A) inhibitors, in compositions and methods for treating or preventing adiposity including adiposity- related conditions such as obesity, type II diabetes, adipose inflammation, metabolic dysfunction, cardiovascular diseases and more generally, metabolic syndrome.

BACKGROUND OF THE INVENTION

[0002] Obesity is a complex chronic condition in which excess adiposity predisposes the interacting metabolic and immune systems to continuous stress (Gregor and Hotamisligil, 201 1 ; Horng and Hotamisligil, 201 1 ; Hotamisligil, 2006; Iyer et al, 2010). Among the dynamic components of adipose tissue are adipocytes as well as many different cells including endothelial cells, fibroblasts and immune cells such as macrophages, monocytes, T-cells and mast cells that contribute indirectly to adipocyte function (Feuerer et al, 2009; Liu et al, 2009; Nishimura et al, 2009). Stress caused by nutritional overload is associated with initial infiltration of neutrophils, T-cells and mast cells into adipose, followed during chronic overload by macrophages and activation of resident macrophages, leading to adipocyte dysfunction together with the metabolic and cardiovascular abnormalities that characterize metabolic syndrome (Feuerer et al. , 2009; Iyer et al. , 2010; Kosteli et al. , 2010; Liu et al , 2009; Nishimura et al, 2009).

[0003] Genetic ablation or chemical intervention that reduces immune cell infiltration or action in adipose tissue can prevent or treat diet-induced obesity in rodents (Feuerer et al , 2009; Kosteli et al, 2010; Liu et al, 2009; Nishimura et al, 2009). Recent studies implicate novel roles for immune cells such as macrophages in regulating lipolysis during diet-induced obesity (Kosteli et al, 2010). Weight loss induced by calorie restriction is also associated with a rapid, temporary recruitment of macrophages to white adipose tissue indicating a role for macrophages as transporters of fatty acid during lipolysis (Kosteli et al, 2010). Macrophages were predicted to facilitate the trafficking of lipids from white adipose tissue probably to the liver for metabolism based on the transient recruitment patterns and the expression of scavenger receptors and lipid-handling genes (Kosteli et al, 2010; Red Eagle and Chawla, 2010). However, precise mechanisms for macrophage regulation of adipose tissue lipolysis remain unknown. Whether macrophages and other immune cells exert endocrine or paracrine control of adipocytes in order to regulate lipolysis in diet-induced obesity is yet to be elucidated (Red Eagle and Chawla, 2010). Pharmaceutical interventions to decrease fat stores in adipose tissue to improve adipocyte function by stimulating lipolysis and oxidation of the released fatty acids are currently being investigated (Langin, 2006).

[0004] Lipolysis in adipose tissue is tightly regulated by hormones or enzymes leading to the hydrolysis of triglycerides to free fatty acids and glycerol (Jaworski et al, 2009a). Inflammatory cells such as mast cells, neutrophils and macrophages express phospholipase A ₂ (PLA ₂ ) isozymes that are involved in various physiological processes, including lipid metabolism and cellular signaling (Jaworski et al, 2009a; Scott et al, 1991). Adipose-specific phospholipase A2 (pla2gl 6) and prostaglandin E2 (PGE ₂ ) may play important autocrine and paracrine roles in ob/ob and db/db knockout mice in regulating lipolysis through a PGE ₂ -EP3-cAMP pathway (Duncan et al., 2008; Jaworski et al, 2009a). PGE ₂ is strongly linked to anti-lipolytic responses in adipocytes by acting through the Goci-coupled EP3 receptor and stimulation of leptin (Jaworski et al., 2009a; Kim and Moustaid-Moussa, 2000; Strong et al, 1992). However, secretory phospholipase A ₂ group Ila (PLA2G2A) is mainly recognized for its role in chronic inflammatory diseases and generation of prostaglandin PGE ₂ and other eicosanoids following immune cell activation (Reddy and Herschman, 1996; Scott et al, 1991 ; Wery et al, 1991), but not for activity in adipose tissues.

[0005] In work leading up to the present invention, the role of PLA2G2A and the therapeutic potential of its inhibition in adipose tissue were investigated during diet-induced obesity, in a rat model relevant to human disease. The present inventors surprisingly discovered that

PLA2G2A (at both the mRNA and protein level) was selectively and significantly upregulated in adipose tissue of rats that were fed a diet high in carbohydrates and saturated fats (HCHF), as compared to the adipose tissue of rats fed a more normal nutritional diet of corn starch (CS). Of several other PLA ₂ isozymes examined, including the adipose-specific phospholipase A ₂ (PLA2G16), most were hardly affected by the different diets. Furthermore, inhibition of PLA2G2A by an orally administered compound reversed and protected against adiposity, adipose inflammation and metabolic dysfunction in diet-induced obese rats, and these effects were traced in part to PGE ₂ -cAMP regulation that is linked to promoting lipolysis to enhance fat utilization and energy expenditure. The pharmacological responses of PLA2G2A inhibition were found not to be related to direct effects on adipocytes, but rather to effects on immune cells, including macrophages, that infiltrate the stromal vascular fraction of adipose tissue during development of chronic obesity. This inhibition of

PLA2G2A restored and stimulated cyclic AMP (cAMP) levels and affected other markers such as

PGE ₂ concentrations associated with a pathway leading to lipolysis in adipose tissue. In particular, an inhibitor of PLA2G2A administered to HCHF fed rats resulted, relative to untreated HCHF fed rats, in: (i) reduced total body mass, (ii) reduced abdominal fat pad mass, (iii) reduced adipose tissue inflammation, (iv) reduced insulin intolerance and resistance including insulin resistance syndrome, (v) reduced glucose intolerance, (vi) a reduction in or inhibition in the elevation of macrophages infiltrating into adipose tissue, (vii) reduced PGE ₂ levels in serum and/or adipose tissue, (viii) prevention of diet-induced cardiovascular abnormalities such as cardiac fibrosis and remodeling in the heart, and (ix) reduced PGE2 release from immune cells.

[0006] The results establish a novel strategy for mitigating effects of diet induced metabolic syndrome in the form of using inhibitors of the enzyme PLA2G2A that is found in both humans and rodents and evidently has an important role in mediating the regulation in vivo of immune cells that impact substantially on diet-induced development of adiposity-related conditions. The present inventors propose, therefore, that inhibitors of sPLA ₂ enzymes, and including those that can influence the concentrations and activities of PLA2G2A, are useful in methods and compositions for treating or preventing adiposity-related conditions including obesity, type II diabetes, metabolic dysfunction and cardiovascular diseases that characterize metabolic syndrome, as described hereafter.

SUMMARY OF THE INVENTION

[0007] Accordingly, in one aspect, the present invention comprises methods for (1) reducing total body mass, (2) reducing adipose tissue inflammation, (3) reducing insulin intolerance or resistance, (4) reducing glucose intolerance, (5) reducing or inhibiting elevation of macrophage numbers infiltrating into adipose tissue, (6) reducing PGE2 levels in adipose tissue and/or plasma, (7) preventing cardiovascular abnormalities such as cardiac fibrosis and remodeling in the heart, and (8) reducing PGE2 release from adipose immune cells in a subject. These methods generally comprise, consist or consist essentially of reducing or inhibiting the activity of a PLA2G2A produced by an immune cell (e.g., a macrophage, monocyte, dendritic cell, T-cell, B-cell, natural killer (NK) cell, neutrophil, eosinophil or mast cell) that infiltrates, is contained in or is otherwise associated with plasma, adipose tissue or fat deposits in organs, muscles, or other tissues of the subject. Suitably, the PLA2G2A is aberrantly expressed (e.g., a detected up-regulation or increase in the level or functional activity of the PLA2G2A) in the immune cell in response to a high fat diet (e.g., a HCHF diet) or to an adiposity-related condition.

[0008] In related aspects, the present invention provides methods for reducing increased adiposity in response to a high fat diet or for protecting against diet-induced metabolic syndrome in a subject. These methods generally comprise, consist or consist essentially of administering to the subject a PLA2G2A inhibitor in an amount and under conditions effective for inhibiting PLA2G2A in cells and/or reducing PGE ₂ release from an immune cell (also referred to herein as "adipose immune cell") that infiltrates, is contained in or is otherwise associated with adipose tissue of the subject. In specific embodiments the PLA2G2A inhibitor is a selective inhibitor of one or more functions of PLA2G2A.

[0009] Another aspect of the present invention provides PLA2G2A inhibitors (e.g., selective inhibitors of PLA2G2A), which reduce or inhibit the activity of a PLA2G2A produced by an immune cell that infiltrates, is contained in or is otherwise associated with adipose tissue for controlling adiposity in a subject, including use in the treatment or prevention of adiposity-related conditions (e.g., obesity and conditions of localized, abnormal increases in adiposity such as, but not limited to, lipoma and lipomatosis, as well as type II diabetes, insulin resistance syndrome, metabolic dysfunction, cardiovascular diseases such as arteriosclerosis and vascular inflammation and more generally, metabolic syndrome). Non limiting examples of suitable PLA2G2A inhibitors include nucleic acids such as PLA2G2A antisense molecules and siRNA, amino acid inhibitors, aptamers, antibodies, peptides as well as small molecule organic inhibitors of PLA2G2A. Any compound that inhibits PLA2G2A, either directly or indirectly, and suitably at millimolar inhibitor concentrations or below in vitro, or at 100 mg/kg/day inhibitor doses or below in vivo, would be considered to be capable of exerting the properties of PLA2G2 inhibitors that are useful in the practice of the present invention.

[0010] In yet another aspect, the present invention provides compositions for controlling adiposity, including use in the treatment or prevention of adiposity-related conditions. These compositions generally comprise, consist or consist essentially of a PLA2G2A inhibitor (e.g., a selective PLA2G2A inhibitor), which suitably reduces or inhibits the activity of a PLA2G2A produced by an immune cell that infiltrates, is contained in or is otherwise associated with adipose tissue, or with fat tissue in muscles, organs or tissues, or with plasma, and a pharmaceutically acceptable carrier. The compositions may be administered by injection, by topical or mucosal application, by inhalation or via the oral route including modified-release modes of administration, over a period of time and in amounts which are effective to ameliorate, inhibit or otherwise reduce adiposity and/or to treat or prevent the adiposity related condition. In specific embodiments, the composition is administered orally.

(0011) Thus, in a related aspect, the present invention provides methods for controlling adiposity, including in the treatment or prevention of adiposity-related conditions (e.g., obesity and conditions of localized, abnormal increases in adiposity such as, but not limited to, lipoma and lipomatosis, as well as type II diabetes, insulin resistance syndrome, metabolic dysfunction, cardiovascular diseases such as atherosclerosis or arteriosclerotic vascular disease and vascular inflammation, and more generally, metabolic syndrome), in a subject. These methods generally comprise, consist or consist essentially of administering to the subject an effective amount of a PLA2G2A inhibitor (e.g., a selective inhibitor of PLA2G2A), which reduces or inhibits the activity of PLA2G2A produced by an immune cell that infiltrates, is contained in or is otherwise associated with adipose tissue, and optionally a pharmaceutically acceptable carrier.

[0012] Still another aspect of the present invention provides the use of a PLA2G2A inhibitor (e.g., a selective PLA2G2A inhibitor), which suitably reduces or inhibits the activity of a PLA2G2A produced by an immune cell that infiltrates, is contained in or is otherwise associated with adipose tissue in the preparation of a medicament for controlling adiposity including treating or preventing an adiposity-related condition. [0013] In yet another aspect, the present invention provides a compound of formula (IB):

[0014] wherein:

[0015] X is selected from the group consisting of:

[0016] CRR'-tetrazolyl, CRR'S0 ₃ H, CRR' P(0)(OH) ₂ , CRR' P(0)(OH)(OR"), CHRCH ₂ C0 ₂ H, CHRCH ₂ -tetrazolyl, CHRCH ₂ S0 ₃ H, CHRCH ₂ P(0)(OH) ₂ , CHRCHjP(0)(OH)(OR"), OP(0)(OH)R', NRSO ₃ H, NRP(0)(OH) ₂ , NRP(0)(OHXOR")

[0017] wherein R, R' and R" are independently selected from hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted acyl, optionally substituted arylalkyl, optionally substituted cycloalkylalkyl and optionally substituted heterocyclylalkyl, except that R" is not hydrogen;

[0018] Q is a group selected from formulae (a)-(g):

[0100]

(d) (e) (f) (g)

[0019] R ₁₀₀ is optionally substituted cycloalkyl;

[0020] Z is a group selected from formulae (i)-(iv):

[0021] (i) -(CH ₂ ) _m -aa-(CH ₂ ) _n -B; or [0022] (ii) -(CH ₂ ) _m -aa-(CH ₂ ) _n -A-(CH ₂ ) ₀ -B; or

[00231 (ii -(CH ₂ )p-A-(CH ₂ ) _q -A'-(CH ₂ ) _r -B

[0024] (iv) -(CH ₂ ) _S -B

[0025] wherein

[0026] m is 0 or 1, n, o, p, q and r are independently selected from 0 to 15 and s is from 5 to 15,

[0027] aa is an amino acid side chain residue;

[0028] A and A' are independently selected from O, S, NH, NR, NHC(O), NRC(O), CH ₂ , CHR, CHNH ₂₎ C(O), C(0)0, C(0)NH, OC(O), and CH=CH, wherein R is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted arylalkyl, optionally substituted cycloalkylalkyl and optionally substituted heterocyclylalkyl;

[0029] B is selected from, hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted cycloalkyl, optionally substituted aryloxy, and optionally substituted heterocyclyloxy; optionally substituted cycloalkyloxy, C0 ₂ H; and

[0030] wherein m, n, o, p, q, r, s, aa, A, A' and B are such that the longest continuous chain of atoms in a group of formula (i)-(iv) is from 5 to 15 atoms long;

[0031] or salt, derivative or prodrug thereof.

[0032] In a related aspect, the present invention provides pharmaceutical compositions comprising a compound of formula (IB) and a pharmaceutically acceptable carrier.

BRIEF DESCRIPTION OF THE DRAWINGS

[0033] Figure 1 is a graphical and photographic representation showing RT-PCR gene expression of different PLA2 enzymes and protein expression of PLA2G2A in rat adipose tissue. (A) Quantitative comparison of mRNA expression level of PLA2 enzymes in corn starch (CS) and high carbohydrate high fat (HCHF) adipose tissue. Values of PLA2 mRNA levels were normalized relative to 18S rRNA. (B) Immunoblot of PLA2G2A protein levels in adipose tissue with GAPDH used as a loading control. Each lane represents adipose tissue homogenate from a single rat. Optical density of protein bands was determined using ImageJ software. (C) Serum and (D) adipose concentrations of PGE2 from CS versus HCHF fed rats. Values of PLA2 mRNA levels were normalized relative to 18S rRNA. Error bars represent means + SEM (n=3-5 animals). * P <0.05, **P <0.01, *** P <0.001 , NS; not significant. [0034] Figure 2 is a graphical and photographic representation showing that a PLA2G2A inhibitor, KH064, modulates diet-induced adiposity in vivo in rats. (A) Daily body weights for HCHF- fed rats (n= 10) alone or with daily oral treatment from weeks 9- 16 with H064 (HCHF+ H064, n=10). (B) Cumulative percentage weight gain for HCHF-fed rats (n=10) alone or with daily oral treatment from weeks 9- 16 with KH064 (HCHF+KH064, n= 10). (C) Representative photographs showing comparison of visceral fat in rats at 16 weeks after corn starch or HCHF diets together with no drug treatment or with daily treatment of KH064 at 5mg/kg/day p.o. from Weeks 9-16 inclusive. (D) Total adiposity and depot specific adiposity for rats from the three different treatment groups (n=6). Error bars are means ± SEM; *P < 0.05, **P < 0,01, ***P < 0.001.

[0035] Figure 3 is a graphical representation showing that KH064 treatment modulates

PGE2 concentrations in Wistar rats and stromal vascular cells. PGE2 concentrations in serum (A) and whole adipose tissue (B) from rats fed a high carbohydrate high fat (HCHF) diet alone or with drug ( H064) in accordance with Figure 2. (C). Pla2g2a gene expression in whole adipose tissue, and component adipocytes versus stromal vascular cells (SVC) fractions. (D) Ex vivo treatment with KH064 as per Figure 2 inhibits LPS-induced PGE2 production in SVC. Error bars represent mean ± SEM of least three independent experiments. *P <0.05, **P <0.01, *** P <0.001, NS; not significant.

[0036] Figure 4 is a graphical representation showing that KH064 inhibits palmitic acid- induced PGE2 production in vitro in different human immune cells. The production of PGE2 in culture supernatants was analyzed by ELISA. (A) Human monocyte-derived macrophages (HMDM), (B) peripheral blood mononuclear cells (PBMC), (C) Jurkat, (D) HMC-1 and (E) THP-1 secrete PGE2 elicited by palmitic acid (PA) and pre-treatment of KH064 (10 μΜ) inhibits this palmitic acid-induced PGE2 production. Error bars represent mean ± SEM of least three independent experiments. *P <0.05, **P <0.01, *** P <0.001.

[0037] Figure 5 is a graphical representation showing in vivo responses of KH064 (5 mg/kg day p.o. administered weeks 9-16 inclusive) on the regulation of metabolic parameters that were elevated in Wistar rats fed on HCHF versus CS diets for 16 weeks. (A) Immunoblot of phosphor- HSL (Ser563) in adipose tissue with total HSL as the loading control. Optical density of protein bands was determined using ImageJ software. (B) RT-PCR gene expression of genes in adipose tissue of rats fed CS and HCHF diets with and without KH064 treatment. (C) Plasma concentrations for lipids non- esterified fatty acids (NEFA), triglycerides and total cholesterol in rats of different groups (n=5-10). (D) Liver total lipid content in rats of different groups (n=5). (E) Plasma liver enzymes in rats of . different groups (n=5-10). (F) Total soluble fecal fat in rats of different groups (n=5). (G and H) RT- PCR gene expression of different metabolic genes in liver and skeletal muscle respectively.

Quantitative comparison of mRNA expression level of metabolic genes in corn starch (CS) and high carbohydrate high fat (HCHF) with and without KH064 treatment in liver (E) and skeletal muscle (F). Values of mRNA levels were normalized relative to 18S rRNA. Error bars represent means ± SEM (n=3-5 animals). * P <0.05, **P <0.01, *** P O.001, NS; not significant.

[0038] Figure 6 is a graphical and photographic representation showing in vivo responses of KH064 (5 mg kg day p.o. administered weeks 9-16 inclusive) on the regulation of metabolic parameters that were elevated in rats fed on HCHF versus CS diets for 16 weeks. (A) RT-PCR analysis of glucose metabolism genes in rat pancreas of different groups. (B) Plasma concentrations of insulin in rats of different groups (n=5). (C) Fasting blood glucose concentrations in rats of different groups (n=6 for all groups). (D) Oral glucose tolerance tests (OGTT) in rats of different groups (n=6 for all groups). (E) Insulin tolerance test (ITT) in rats of different groups (n=6 for all groups). (F) Representative images (40X magnification) of interstitial collagen deposition in the left ventricle and (G) quantitative measurement of the area of collagen deposition in the interstitial region of the left ventricle (n=4 for all groups). (H) Diastolic stiffness constant of rats in different groups. Error bars represent means ± SEM (n=3-5 animals). * P O.05, **P <0X)1, *** P <0.001 , NS; not significant.

[0039] Figure 7 is a graphical and photographic representation showing RT-PCR analysis and immunohistochemistry of adipose tissue from the three treatment groups (as per Figure 2) of rats at 16 weeks. (A) Levels of pla2gl6 mRNA in rat adipose tissue, adipocyte and stromal vascular cells (SVC) fractions, were expressed relative to 18s rRNA. (B) levels of pla2gl6 mRNA in epididymal fat from mice maintained on a standard chow diet (lean) or a high fat diet (obese) for 16 weeks. Pla2gl6 mRNA levels v ere standardized using cyclophilin. (C) Representative images showing EDI positive crown-like structures in rat adipose tissue and (D) quantitative measurements of EDI positive crownlike structures. (E) Ml -specific genes and (F) M2-specific genes in rat adipose tissue from different groups. Error bars represent means ± SEM (n=3-5 animals). * P <0.05, **P <0.01, NS; not significant.

[0040] Figure 8 is a graphical representation showing that PGE2 regulates intracellular cAMP and glycerol release (lipolysis) in vitro, (a) PGE2 regulates cAMP levels of 3T3-L1 mouse adipocytes through activation of EP3 receptors. Stimulation by PGE2 (10 pg mL) leads to inhibition of cAMP relative to forskolin (500 nM). Pre-treatment with selective EP3 receptor antagonist, L798106 ( 1 uM), restores cAMP levels, (b) Pertussis toxin (PTX) treatment (300 ng/mL) prevented PGE2- mediated cAMP inhibition, (c) PGE2 (10 pg mL) decreases glycerol release (lipolysis) in rat adipose tissue. Error bars represent means ± SEM of at least three independent experiments. ***P <0.001. ( [0041] Figure 9 is a graphical representation showing the concentration-dependent inhibition by KH064 of PLA2 enzymatic activity from adipose tissue isolated from CS-fed rat.

Catalytically active PLA2 activity in adipose tissue was based on the hydrolysis of substrate (1,2- dithio analogue of diheptanoyl phosphatidylcholine). The free thiol released then coupled with 5,5'- dithio-bis-(2-nitrobenzoic acid) and the colorimetric change was measured spectrophotometrically at 405 nm. [0042] Figure 10 is a graphical representation showing that H064 modulates LPS- induced PGE2 production in vitro in human immune cells. Pre-treatment of human monocyte derived macrophages (HMDM), peripheral blood mononuclear cells (PBMC) and HMC-1 cells with H064 (10 μΜ) inhibited LPS-induced PGE2 production. Jurkat and THP-1 failed to induce PGE2 production from LPS stimulation. Error bars represent mean ± SEM of least three independent experiments. *** P <0.001.

[0043] Figure 1 1 is a photographic and graphical representation showing liver structure and function for the three treatment groups of Figure 2. Representative histological pictures of the liver lipid deposition at 20x (top row) and 40x (bottom row) magnification (A) and plasma bilirubin concentrations (B).

[0044] Figure 12 is a graphical representation showing in vivo responses of KH064 on the regulation of cardiovascular parameters that were significantly elevated in rats on HCHF versus CS diets. (A) Systolic blood pressure in rats of different groups (n=6 for all groups). (B) Fractional shortening and ejection fraction percentages in rats of different groups (n=6 for all groups). * P <0.05

[0045] Figure 13 is a graphical representation showing the influence of KH064 on body weight and biochemical markers in plasma of treated rats. (A) Changes in body weight of CS-fed rats with or without KH06 administration over a 16-wk period. (B) Changes in plasma levels of ALT, AST, LDH and ALP of CS-fed rats with or without H064 administration. NS: not significant.

DETAILED DESCRIPTION OF THE INVENTION

/. Definitions

[0046] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which the invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, preferred methods and materials are described. For the purposes of the present invention, the following terms are defined below.

[0047] The articles "a" and "an" are used herein to refer to one or to more than one (i.e. to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

[0048] By "about" is meant a quantity, level, value, number, frequency, percentage, dimension, size, amount, weight or length that varies by as much 15, 14, 13, 12, 1 1 , 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 % to a reference quantity, level, value, number, frequency, percentage, dimension, size, amount, weight or length.

[0049] The term "aberrant expression," as used herein to describe the expression of a PLA2G2A gene, refers to the overexpression (at the RNA and/or protein level) of the PLA2G2A gene in immune cells that infiltrate, are contained in, or are otherwise associated with adipose tissue relative to the level of expression of the PLA2G2A gene in corresponding immune cells from a healthy subject or from a subject lacking a high fat diet or an adiposity-related condition. In particular, a PLA2G2A gene is aberrantly expressed in immune cells that infiltrate, are contained in, or are otherwise associated with adipose tissue if the level of expression of the PLA2G2A gene is higher by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90%, or even an at least about 100%, 200%, 300%, 400%, 500%, 600%, 700%, 800%, 900% or 1000%, than the level of expression of the

PLA2G2A gene in corresponding immune cells from a healthy subject or from a subject lacking a high fat diet or an adiposity related condition.

[0050] The term "acyl" denotes a group containing the moiety C=0 (and not being a carboxylic acid, ester or amide or thioester). Preferred acyl includes C(0)-R, wherein R is hydrogen or an alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl, arylalkyl, cycloalkylalkyl or

heterocyclylalkyl residue, suitably a C1.20 residue. Non-limiting examples of acyl include formyl; straight chain or branched alkanoyl such as, acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 2,2-dimethylpropanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, heptadecanoyl, octadecanoyl, nonadecanoyl and icosanoyl; phenylcarbonyl; cycloalkylcarbonyl such as cyclopropylmethyl(or ethyl)carbonyI cyclobutylmethyl(or ethyl)carbonyl, cyc!opentylmethyl(or ethyl)carbonyl and cyclohexylmethyl (or ethyl)carbonyl; alkanoyl such as phenylalkanoyl (e.g., phenylacetyl, i.e., benzoyl, phenylpropanoy!, phenylbutanoyl, phenylpentanoyl, phenylhexanoyl) and naphthylalkanoyl (e.g., naphthylacetyl, naphthylpropanoyl and naphthylbutanoyl), and phenylalkenoyl (e.g., phenylhex- 4-en-oyl, phenylhex-3-en-oyl, phenylheptanoyl, phenylhept-4-en-oyl, phenylhept-3-en-oyl).

[0051] "Adiposity" is used herein to refer to increased fat mass or an accumulation of excess fat mass.

[0052] As used herein, the term "adiposity-related condition" refers to conditions associated with increased fat mass or an accumulation of excess fat mass whether distributed throughout the body or in different parts of the body or localized to particular tissues of the body or body parts. The term "adiposity-related condition" includes and encompasses obesity as well as abnormal increases in adiposity such as, but not limited to, lipoma and lipomatosis, and related conditions such as type II diabetes, insulin resistance syndrome, metabolic dysfunction, cardiovascular diseases such as arteriosclerosis, vascular inflammation and metabolic syndrome).

[0053] The term "alkenyl" as used herein denotes groups formed from straight chain or branched hydrocarbon residues containing at least one carbon to carbon double bond including ethylenically mono-, di- or poly-unsaturated alkyl groups as defined herein, suitably C _\ . ₂ o alkenyl (e.g., Ci-io or C]^). Examples of alkenyl include vinyl, allyl, 1 -methylvinyl, butenyl, iso-butenyl, 3-methyl- 2-butenyl, 1 -pentenyl, cyclopentenyl, 1-methyl-cyclopentenyl, 1 -hexenyl, 3-hexenyI, cyclohexenyl, 1 - heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 3-hexenyl, 4-hexenyl, 1-octenyl, cyclooctenyl, 1- nonenyl, 2-nonenyl, 3-nonenyl, 1-decenyl, 3-decenyl, 1,3-butadienyl, l-4,pentadienyl, 1 ,3- cyclopentadienyl, 1,3-hexadienyl, and 1 ,4-hexadienyl. An alkenyl group may be optionally substituted by one or more optional substituents as herein defined. Accordingly, "alkenyl" as used herein is taken to refer to optionally substituted alkenyl.

[0054] As used herein, the term "alkyl," when used alone or in words such as "arylalkyl," "heterocyclylalkyl" and "cycloalkylalkyl," denotes straight chain or branched hydrocarbon residues, suitably C|. ₂₀ alkyl, e.g., chain and branched alkyl include methyl,

ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, amyl, isoamyl, sec-amyl, 1 ,2- dimethylpropyl, 1,1-dimethyl-propyl, hexyl, 4-methylpentyl, 1-methylpentyl, 2-methylpentyl, 3- methylpentyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1 ,2-dimethylbutyl, 1 ,3- dimethylbutyl, 1 ,2,2,-trimethylpropyl, 1 , 1 ,2-trimethylpropyl, heptyl, 5-methoxyhexyl, 1 -methylhexyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 4,4-dimethylpentyl, 1 ,2-dimethylpentyl, 1,3-dimethylpentyl, 1,4-dimethyl-pentyl, 1,2,3-trimethylbutyl, 1,1,2-trimethylbutyl, 1 , 1 ,3-trimethylbutyl, octyl, 6- methylheptyl, 1 -methylheptyl, 1,1,3,3-tetramethylbutyl, nonyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-methyl-octyl, 1-, 2-, 3-, 4- or 5-ethylheptyl, 1-, 2- or 3-propylhexyl, decyl, 1-, 2-, 3-, 4-, 5-, 6-, 7- and 8- methylnonyl, 1 -, 2-, 3-, 4-, 5- or 6-ethyloctyl, 1-, 2-, 3- or 4-propylheptyl, undecyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-methyldecyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-ethylnonyl, 1-, 2-, 3-, 4- or 5-propylocytl, 1 -, 2- or 3- butylheptyl, 1-pentylhexyl, dodecyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9- or 10-methylundecyl, 1-, 2-, 3-, 4-, 5-, 6-, 7- or 8-ethyldecyl, 1-, 2-, 3-, 4-, 5- or 6-propylnonyl, 1-, 2-, 3- or 4-butyloctyl, 1-2-pentylheptyl and the like. An alkyl group may be optionally substituted by one or more optional substituents as herein defined. Accordingly, "alkyl" as used herein is taken to refer to optionally substituted alkyl.

[0055] The term "alkynyl" denotes groups formed from straight chain or branched hydrocarbon residues containing at least one carbon to carbon triple bond including ethynyically mono-, di- or poly-unsaturated alkyl or cycloalkyl groups as defined herein, suitably Ci. ₂ o alkynyl

(e.g., CMO or Examples, include ethynyl, propynyl, butynyl, pentynyl. An alkynyl group may be optionally substituted by one or more optional substituents as herein defined. Accordingly, "alkynyl" as used herein is taken to refer to optionally substituted alkynyl.

[0056] The term "aryl" used either alone or in compounds words such as "arylalkyl" and "aryloxy," denotes single, polynuclear, conjugated or fused residues of aromatic hydrocarbons.

Examples of aryl include phenyl, biphenyl and naphthyl. In specific embodiments, aryl groups include phenyl and naphthyl. An aryl group may be optionally substituted by one or more optional substituents as herein defined. Accordingly, "aryl" as used herein is taken to refer to aryl that may be optionally substituted, such as optionally substituted phenyl and optionally substituted naphthyl.

[0057] The terms "arylalkyl," "cycloalkylalkyl" and "heterocyclylalkyl" refer to an alkyl group substituted (suitably terminally) by an aryl, cycloalkyl or heterocyclyl group, respectively, [0058] The terms "aryloxy," "cycloalkyloxy" and "heterocyclyloxy" denote aryl, cycloalkyl and heterocyclyl groups, respectively, when linked by an oxygen atom.

[0059] The terms "complementary" and "complementarity" refer to polynucleotides (i.e., a sequence of nucleotides) related by the base-pairing rules. For example, the sequence "A-G-T," is complementary to the sequence "T-C-A." Complementarity may be "partial," in which only some of the nucleic acids' bases are matched according to the base pairing rules. Or, there may be "complete" or "total" complementarity between the nucleic acids. The degree of complementarity between nucleic acid strands has significant effects on the efficiency and strength of hybridization between nucleic acid strands.

[0060] Throughout this specification, unless the context requires otherwise, the words

"comprise," "comprises" and "comprising" will be understood to imply the inclusion of a stated step or element or group of steps or elements but not the exclusion of any other step or element or group of steps or elements. Thus, use of the term "comprising" and the like indicates that the listed elements are required or mandatory, but that other elements are optional and may or may not be present. By "consisting of is meant including, and limited to, whatever follows the phrase "consisting of. Thus, the phrase "consisting of indicates that the listed elements are required or mandatory, and that no other elements may be present. By "consisting essentially of is meant including any elements listed after the phrase, and limited to other elements that do not interfere with or contribute to the activity or action specified in the disclosure for the listed elements. Thus, the phrase "consisting essentially of indicates that the listed elements are required or mandatory, but that other elements are optional and ' may or may not be present depending upon whether or not they affect the activity or action of the listed elements.

[0061] "Cycloalkyl" when used alone or , in compound words such as "cycloalkoxy," refers to cyclic hydrocarbon residues, including mono- or polycyclic alkyl groups. Exemplary cycloalkyl are C4.7 alkyl. A "cycloalkyl" group may contain one or more double or triple bonds to form a cycloalkenyl or cycloalkynyl group and accordingly, "cycloalkyl" also refers to non-aromatic unsaturated as well as saturated cyclic hydrocarbon residues. Examples of "cycloalkyl" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, 1,3-cyclohexadienyl, 1 ,4-cyclohexadienyl, 1,3-cycloheptadienyl, 1,3,5-cycloheptatrienyI and 1,3,5,7- cyclooctatetraenyl. A cycloalkyl group may be optionally substituted by one or more optional substituents as herein defined. Accordingly, "cycloalkyl" as used herein is taken to refer to optionally substituted cycloalkyl.

[0062] The phrase "conditions of localized, abnormal increases in adiposity" as used herein includes pathologies characterized by and/or associated with anatomically localized, disregulated adiposity that lead to circumscribed depositions of fat tissue. Such conditions include but are not limited to lipoma and lipomatosis. (0063] By "corresponds to" or "corresponding to" is meant a nucleic acid sequence that displays substantial sequence identity to a reference nucleic acid sequence or an amino acid sequence that displays substantial sequence similarity or identity to a reference amino acid sequence. In general the nucleic acid sequence will display at least about 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 97, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99% or even up to 100% sequence identity to the reference nucleic acid sequence, or the amino acid sequence will display at least about 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 97, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99% or even up to 100% sequence similarity or identity to the reference amino acid sequence.

[0064] By "effective amount", in the context of modulating an activity or of treating or preventing a condition is meant the administration of that amount of agent to an individual in need of such modulation, treatment or prophylaxis, either in a single dose or as part of a series, that is effective for modulation of that effect or for treatment or prophylaxis or improvement of that condition. Non- limiting examples of such improvements in an individual suffering conditions of localized, abnormal increases in adiposity include reduced fat deposits, increased leanness, weight loss and an

improvement in the symptoms relating to cardiovascular disease and diabetes. The effective amount will vary depending upon the health and physical condition of the individual to be treated, the taxonomic group of individual to be treated, the formulation of the composition, the assessment of the medical situation, and other relevant factors. It is expected that the amount will fall in a relatively broad range that can be determined through routine trials.

[0065] By "gene" is meant a unit of inheritance that occupies a specific locus on a chromosome and consists of transcriptional and/or translational regulatory sequences and/or a coding region and/or non-translated sequences (i.e., introns, 5' and 3' untranslated sequences).

[0066] "Glucose intolerance" refers to insufficiency of insulin secretion response due to glucose load and/or reduction of insulin action in skeletal muscles or adipose tissues. In many cases, glucose intolerance is caused by insulin resistance. Glucose intolerance is regarded as a condition that precedes the onset of diabetes and is multiply associated with various metabolic diseases (obesity, hypertension, hypertriglyceridemia and the like).

[0067] The term "group" as applied to chemical species refers to a set of atoms that forms a portion of a molecule. In some instances, a group can include two or more atoms that are bonded to one another to form a portion of a molecule. A group can be monovalent or polyvalent (e.g., bivalent) to allow bonding to one or more additional groups of a molecule. For example, a monovalent group can be envisioned as a molecule with one of its hydrogen atoms removed to allow bonding to another group of a molecule. A group can be positively or negatively charged. For example, a positively charged group can be envisioned as a neutral group with one or more protons (i.e., FT) added, and a negatively charged group can be envisioned as a neutral group with one or more protons removed.

Non-limiting examples of groups include, but are not limited to, alkyl groups, alkylene groups, alkenyl groups, alkenylene groups, alkynyl groups, alkynylene groups, aryl groups, arylene groups, iminyl groups, iminylene groups, hydride groups, halo groups, hydroxy groups, alkoxy groups, carboxy groups, thio groups, alkylthio groups, disulfide groups, cyano groups, nitro groups, amino groups, alkylamino groups, dialkylamino groups, silyl groups, and siloxy groups. Groups such as alkyl, alkenyl, alkynyl, aryl, and heterocyclyl, whether used alone or in a compound word or in the definition of a group may be optionally substituted by one or more substituents. "Optionally substituted," as used herein, refers to a group may or may not be further substituted with one or more groups selected from alkyl, alkenyl, alkynyl, aryl, halo, haloalkyl, haloalkenyl, haloalkynyl, haloaryl, hydroxy, alkoxy, alkenyloxy, aryloxy, benzyloxy, haloalkoxy, haloalkenyloxy, haloaryloxy, nitro, nitroalkyl, nitroalkenyl, nitroalkynyl, nitroaryl, nitroheterocyclyl, amino, alkylamino, dialkylamino,

alkenylamino, alkynylamino, arylamino, diarylamino, phenylamino, diphenylamino, benzylamino, dibenzylamino, hydrazino, acyl, acylamino, diacylamino, acyloxy, heterocyclyl, heterocycloxy, heterocyclamino, haloheterocyclyl, carboxy ester, carboxy, carboxy amide, mercapto, alkylthio, benzylthio, acylthio and phosphorus-containing groups. As used herein, the term "optionally substituted" may also refer to the replacement of a CH ₂ group with a carbonyl (C=0) group. Non- limiting examples of optional substituents include alkyl, preferably C].s alkyl (e.g., C _h alky! such as methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), hydroxy C|.g alkyl (e.g., hydroxymethyl, hydroxyethyl, hydroxypropyl), alkoxyalkyl (e.g., methoxymethyl,

methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, ethoxypropyl etc.) Ci.8 alkoxy, (e.g., alkoxy such as methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy), halo (fluoro, chloro, bromo; iodo), trifluoromethyl, trichloromethyl, tribromomethyl, hydroxy, phenyl (which itself may be further substituted, by an optional substituent as described herein, e.g., hydroxy, halo, methyl, ethyl, propyl, butyl, methoxy, ethoxy, acetoxy, amino), benzyl (wherein the CH ₂ and/or phenyl group may be further substituted as described herein), phenoxy (wherein the CH ₂ and or phenyl group may be further substituted as described herein), benzyloxy (wherein the CH ₂ and/or phenyl group may be further substituted as described herein), amino, Ci.g alkylamino (e.g., C _h alky!, such as methylamino, ethylamino, propylamine), di Q.g alkylamino (e.g., Ci-ealkyl, such as dimethylamino, diethylamino, dipropylaminq), acylamino (e.g., NHC(0)CH ₃ ), phenylamino (wherein phenyl itself may be further substituted as described herein), nitro, formyl, -C(0)-Ci. ₈ alkyl (e.g., alkyl, such as acetyl), O- C(0)-alkyl (e.g., C|. ₆ alkyl, such as acetyloxy), benzoyl (wherein the CH ₂ and/or phenyl group itself may be further substituted), replacement of CH ₂ with C=0, C0 ₂ H, C0 ₂ Ci _-8 alkyl (e.g., Ci_5 alkyl such as methyl ester, ethyl ester, propyl ester, butyl ester), C0 ₂ phenyl (wherein phenyl itself may be further substituted), CONH ₂ , CONHphenyl (wherein phenyl itself may be further substituted as described herein), CONHbenzyl (wherein the CH ₂ and/or phenyl group may be further substituted as described herein),CONH C).g alkyl (e.g., alkyl such as methyl amide, ethyl amide, propyl amide, butyl amide), CONHdi C,. ₈ alkyl (e.g., C,. ₆ alkyl)-

[0068] The term "halogen" refers to fluorine, chlorine, bromine or iodine. [0069] The term "heterocyclic" or "heterocyclyl" or "heterocycle," used either alone or in compound words such as "heterocyclylalkyl" or "heterocyclyloxy" denotes single, polynuclear, conjugated or fused carbocyclic groups wherein at least one carbon atom is replaced by a heteroatom, preferably selected from the group of nitrogen, sulfur and oxygen. Where two or more carbon atoms are replaced, this may be by two or more of the same heteroatom or by different heteroatoms. The heterocyclic group may be aromatic or non-aromatic. An aromatic heterocyclyl group may also be referred to as "heter aryl." A heterocyclic group may be optionally substituted by one or more optional substituents as herein defined. Accordingly, "heterocyclic" or "heterocyclyl" or "heterocycle" as used herein is taken to refer to heterocyclyl or heterocyclyl or heterocycle that may be optionally substituted. Illustrative examples of "heterocyclic," "heterocyclyl" or "heterocycle" include 5-6- membered groups, particularly .nitrogen containing groups. Other illustrative examples of heterocyclic groups include N-containing heterocyclic groups such as unsaturated 3 to 6 membered

heteromonocyclic groups containing 1 to 4 nitrogen atoms, e.g., pyrrolyl, pyrrolinyl, imidazolyl, imidazolinyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl or tetrazolyl; saturated 3 to 6-membered heteromonocyclic groups containing 1 to 4 nitrogen atoms such as pyrrolidinyl, imidazolidinyl, piperidyl, pyrazolidinyl or piperazinyl; condensed saturated or unsaturated heterocyclic groups containing 1 to 5 nitrogen atoms such as indolyl, isoindolyl, indolinyl, isoindolinyl, indolizinyl, isoindolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl,

benzotriazolyl, purinyl, quinazolinyl, quinoxalinyl, phenanthradinyl, phenathrolinyl, phthalazinyl, naphthyridinyl, cinnolinyl, pteridinyl, perimidinyl or tetrazolopyridazinyl; saturated 3 to 6-membered heteromonocyclic groups containing 1 to 3 oxygen atoms, such as tetrahydrofuranyl,

tetrahydropyranyl, tetrahydrodioxinyl; unsaturated 3 to 6-membered hetermonocyclic group containing an oxygen atom such as pyranyl, dioxinyl or furyl; condensed saturated or unsaturated heterocyclic groups containing 1 to 3 oxygen atoms, such as benzofuranyl, chromenyl or xanthenyl; unsaturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms such as thienyl or dithiolyl; unsaturated 3 to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms such as oxazolyl, oxazolinyl, isoxazolyl, furazanyl or oxadiazolyl; saturated 3 to 6- membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms such as morpholinyl; unsaturated condensed heterocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms such as benzoxazolyl or benzoxadiazolyl; unsaturated 3 to 6-membered

heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms such as thiazolyl, thiazolinyl; saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms such as thiazolidinyl, thiomorphinyl; and unsaturated condensed heterocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms such as benzothiazolyl or benzothiadiazolyl.

[0070] "Hybridization" is used herein to denote the pairing of complementary nucleotide sequences to produce a DNA-DNA hybrid or a DNA-RNA hybrid. Complementary base sequences are those sequences that are related by the base-pairing rules. In DNA, A pairs with T and C pairs with G. In RNA U pairs with A and C pairs with G. In this regard, the terms "match" and "mismatch" as used herein refer to the hybridization potential of paired nucleotides in complementary nucleic acid strands. Matched nucleotides hybridize efficiently, such as the classical A-T and G-C base pair mentioned above. Mismatches are other combinations of nucleotides that do not hybridize efficiently.

[0071] The term "hyperinsulinemia" refers to a state in an individual in which the level of insulin in the blood is higher than normal.

[0072J Reference herein to "immuno-interactive" includes reference to any interaction, reaction, or other form of association between molecules and in particular where one of the molecules is, or mimics, a component of the immune system.

[0073] The term "insulin resistance" refers to a state in which a normal amount of insulin produces a subnormal biologic response relative to the biological response in a subject that does not have insulin resistance.

[0074] "Insulin Resistance Syndrome," as used herein, refers to various abnormalities associated with insulin resistance/compensatory hyperinsulinemia, which include the following: some degree of glucose intolerance (impaired fasting glucose and impaired glucose tolerance); dyslipidemia (increased triglycerides, decreased high-density lipoprotein cholesterol (HDL-C), decreased low- density lipoprotein (LDL)-particle diameter (small, dense LDL particles), and increased postprandial accumulation of trig!yceride-rich lipoproteins); endothelial dysfunction (increased mononuclear cell adhesion, increased plasma concentration of cellular adhesion molecules, increased plasma concentration of asymmetric dimethylarginine, and decreased endothelial-dependent vasodilatation); procoagulant factors (increased plasminogen activator inhibitor- 1 and increased fibrinogen);

hemodynamic changes (sympathetic nervous system activity and renal sodium retention); markers of inflammation (increased C-reactive protein, white blood cell count, etc.); abnormal uric acid metabolism (increased plasma uric acid concentration and renal uric acid clearance); increased testosterone secretion (ovary); and sleep-disordered breathing. Further, some of the clinical syndromes associated with insulin resistance include the following: type II diabetes, cardiovascular disease, essential hypertension, polycystic ovary syndrome, nonalcoholic fatty liver disease, certain forms of cancer, and sleep apnea.

[0075] By "linker," is meant a molecule or group of molecules (such as a monomer or polymer) that connects two molecules and often serves to place the two molecules in a desirable configuration.

[0076] "Metabolic Syndrome," as used herein, refers to a combination of medical disorders that increases the risk to a person for cardiovascular disease and diabetes. Other known names referring to such syndrome is syndrome X, insulin resistance syndrome, Reaven's syndrome. Several features of the syndromes include: fasting hyperglycemia, high blood pressure, central obesity (also known as visceral obesity), decreased High Density Lipoprotein (HDL), elevated triglycerides, elevated uric acid levels. Fasting hyperglycemia, listed above, includes diabetes mellitus type II or impaired fasting glucose and impaired glucose tolerance or insulin resistance. Metabolic syndrome is often defined as including central obesity and at least two of the following: (i) impaired glucose tolerance; (ii) elevated fasting glucose; (Hi) insulin resistance;(iv) conditions (i), (ii) and (iii) are often associated with Type 2 diabetes; (v) dyslipidemia (elevated triglycerides and/or reduced high density lipoprotein (HDL, cholesterol); (vi) vascular dysfunction; (vii) atherosclerotic plaques; and (viii) elevated (systolic or diastolic) blood pressure. In addition to metabolic syndrome, the PLA2G2A inhibitors may have indications for pre-diabetic states or type 2 diabetic states.

10077) By "modulating" is meant increasing or decreasing, either directly or indirectly a particular parameter (e.g., the level or activity of a substance, a physiological effect or manifestation, a therapeutic effect or a prophylactic effect). As used herein, modulation of PLA2G2A activity is given its broadest meaning and includes increasing or decreasing, either directly or indirectly (1) total body mass, (2) adipose tissue inflammation; (3) insulin intolerance and resistance, (4) glucose intolerance, (5) number of macrophages infiltrating into adipose tissue, (6) PGE ₂ levels in adipose tissue, (7) cardiovascular abnormalities such as cardiac fibrosis and remodeling in the heart, (8) PGE ₂ release from adipose immune cells, (9) protection against diet-induced metabolic syndrome, or (10) controlling adiposity including in the treatment or prevention of adiposity-related conditions. In certain embodiments, "modulation" or "modulating" means that a desired/selected activity (e.g., PGE2 release from an immune cell, or adiposity in response to a high fat diet, or protection against diet- induced metabolic syndrome) is more efficient (e.g., at least 10%, 20%, 30%, 40%, 50%, 60% or more), more rapid (e.g., at least 10%, 20%, 30%, 40%, 50%, 60% or more), greater in magnitude (e.g., at least 10%, 20%, 30%, 40%, 50%, 60% or more), and/or more easily induced (e.g., at least 10%, 20%, 30%, 40%, 50%, 60% or more) than in the absence of a PLA2G2A inhibitor.

[0078] The term "obesity" as used herein includes conditions where there is an increase in body fat beyond the physical requirement as a result of excess accumulation of adipose tissue in the body. In general, "obesity' refers to an excessively high amount of body fat or adipose tissue in relation to lean body mass. The amount of body fat includes concern for both the distribution of fat throughout the body and the size of the adipose tissue deposits. Body fat distribution can be estimated by skin-fold measures, waist-to-hip circumference ratios, or techniques such as ultrasound, computed tomography, or magnetic resonance imaging. According to the Center for Disease Control and Prevention, individuals with a body mass index (BMI) of 30 or more are considered obese. The term obesity includes, but is riot limited to, the following conditions: adult-onset obesity; alimentary obesity; endogenous or metabolic obesity; endocrine obesity; familial obesity; hyperinsulinar obesity; hyperplastic-hypertrophic obesity; hypogonadal obesity; hypothyroid obesity; visceral obesity;

lifelong obesity; morbid obesity and exogenous obesity. [0079] The term "oligonucleotide" as used herein refers to a polymer composed of a multiplicity of nucleotide residues (deoxyribonucleotides or ribonucleotides, or related structural variants or synthetic analogues thereof) linked via phosphodiester bonds (or related structural variants or synthetic analogues thereof)- Thus, while the term "oligonucleotide" typically refers to a nucleotide polymer in which the nucleotide residues and linkages between them are naturally occurring, it will be understood that the term also includes within its scope various analogues including, but not restricted to, peptide nucleic acids (PNAs), phosphoramidates, phosphorothioates, methyl phosphonates, 2-0- methyl ribonucleic acids, and the like. The exact size of the molecule can vary depending on the particular application. An oligonucleotide is typically rather short in length, generally from about 10 to 30 nucleotide residues, but the term can refer to molecules of any length, although the term

"polynucleotide" or "nucleic acid" is typically used for large oligonucleotides.

|0080] The terms "patient," "subject," "host" or "individual" used interchangeably herein, refer to any subject, particularly a vertebrate subject, and even more particularly a mammalian subject, for whom therapy or prophylaxis is desired. Suitable vertebrate animals that fall within the scope of the invention include, but are not restricted to, any member of the subphylum Chordata including primates (e.g., humans, monkeys and apes, and includes species of monkeys such from the genus Macaca (e.g., cynomologus monkeys such as Macaca fascicular is, and/or rhesus monkeys (Macaca mulatto)) and baboon (Papio ursinus), as well as marmosets (species from the genus Callithrix), squirrel monkeys (species from the genus Saimiri) and tamarins (species from the genus Saguinus), as well as species of apes such as chimpanzees (Pan troglodytes)), rodents (e.g., mice rats, guinea pigs), lagomorphs (e.g., rabbits, hares), bovines (e.g., cattle), ovines (e.g., sheep), caprines (e.g., goats), porcines (e.g., pigs), equines (e.g., horses), canines (e.g., dogs), felines (e.g., cats), avians (e.g., chickens, turkeys, ducks, geese, companion birds such as canaries, budgerigars etc.), marine mammals (e.g., dolphins, whales), reptiles (snakes, frogs, lizards etc.), and fish. A preferred subject is a human in need of treatment or prophylaxis for an adiposity-related condition. However, it will be understood that the aforementioned terms do not imply that symptoms are present.

[0081] By "pharmaceutically acceptable carrier" is meant a solid or liquid filler, diluent, excipient or encapsulating substance that can be safely used in topical or systemic administration to an animal, suitably a mammal, including humans.

[0082] The term "polynucleotide" or "nucleic acid" as used herein designates mRNA,

RNA, cRNA, cDNA or DNA. The term typically refers to polymeric form of nucleotides of at least 10 bases in length, either ribonucleotides or deoxynucleotides or a modified form Of either type of nucleotide. The term includes single and double stranded forms of DNA.

[0083] The terms "polynucleotide variant" and "variant" and the like refer to

polynucleotides displaying substantial sequence identity with a reference polynucleotide sequence or polynucleotides that hybridize with a reference sequence under stringent conditions that are defined hereinafter. These terms also encompass polynucleotides that are distinguished from a reference polynucleotide by the addition, deletion or substitution of at least one nucleotide. Accordingly, the terms "polynucleotide variant" and "variant" include polynucleotides in which one or more nucleotides have been added or deleted, or replaced with different nucleotides. In this regard, it is well understood in the art that certain alterations inclusive of mutations, additions, deletions and substitutions can be made to a reference polynucleotide whereby the altered polynucleotide retains the biological function or activity of the reference polynucleotide. The terms "polynucleotide variant" and "variant" also include naturally occurring allelic variants. ~

[0084] "Polypeptide," "peptide," "protein" and "proteinaceous molecule" are used interchangeably herein to refer to molecules comprising or consisting of a polymer of amino acid residues and to variants and synthetic analogues of the same. Thus, these terms apply to amino acid polymers in which one or more amino acid residues are synthetic non-naturally occurring amino acids, such as a chemical analogue of a corresponding naturally occurring amino acid, as well as to naturally- occurring amino acid polymers.

[0085) The terms "peptide variant" and "polypeptide variant" and the like refer to peptides and polypeptides that are distinguished from a reference peptide or polypeptide by the addition, deletion or substitution of at least one amino acid residue. In certain embodiments, a peptide or polypeptide variant is distinguished from a reference peptide or polypeptide by one or more substitutions, which may be conservative or non-conservative. In certain embodiments, the peptide or polypeptide variant comprises conservative substitutions and, in this regard, it is well understood in the art that some amino acids may be changed to others with broadly similar properties without changing the nature of the activity of the peptide or polypeptide. Peptide and polypeptide variants also encompass peptides and polypeptides in which one or more amino acids have been added or deleted, or replaced with different amino acid residues.

[0086] The term "PLA2G2A inhibitor" is used herein in a broad sense and includes any molecule or compound that partially or fully inhibits, impairs or deactivates one or more biological activities of PLA2G2A, whether in vitro, in situ, in vivo or ex vivo. Examples of such biological activities include reducing release of pro-inflammatory eicosanoids including prostaglandins such as PGE ₂ . A PLA2G2A inhibitor may function in a direct or indirect manner. For instance, a "PLA2G2A inhibitor" may function to partially or fully inhibit, impair or deactivate one or more biological activities of PLA2G2A, in vitro, in situ, in vivo or ex vivo as a result of its direct binding to PLA2G2 A, which causes a reduction in the release of pro-inflammatory eicosanoids including prostaglandins such as PGE ₂ .

[0087] As used herein, the terms "prevent," "prevented," or "preventing," refer to a prophylactic treatment which increases the resistance of a subject to developing the disease or condition or, in other words, decreases the likelihood that the subject will develop the disease or condition as well as a treatment after the disease or condition has begun in order to reduce or eliminate it altogether or prevent it from becoming worse. These terms also include within their scope preventing the disease or condition from occurring in a subject which may be predisposed to the disease or condition but has not yet been diagnosed as having it.

[0088] "Probe" refers to a molecule that binds to a specific sequence or sub-sequence or other moiety of another molecule. Unless otherwise indicated, the term "probe" typically refers to a polynucleotide probe that binds to another polynucleotide, often called the "target polynucleotide", r through complementary base pairing. Probes can bind target polynucleotides lacking complete sequence complementarity with the probe, depending on the stringency of the hybridization conditions. Probes can be labeled directly or indirectly.

[0089] The term "pro-drug" is used in its broadest sense and encompasses those derivatives that are converted in vivo to the compounds of the invention. Such derivatives would readily occur to those skilled in the art, and include, for example, compounds where a free hydroxy , group is converted into an ester derivative.

[0090] As used herein, "racemate" refers to a mixture of enantiomers.

[0091] The terms "salts," "derivatives" and "prodrugs" includes any pharmaceutically acceptable or compatible salt, ester, hydrate, or any other compound which, upon administration to the recipient, is capable of providing (directly or indirectly) a compound of the invention, or an active metabolite or residue thereof. Suitable pharmaceutically acceptable or compatible salts include salts of pharmaceutically acceptable inorganic acids such as hydrochloric, sulfuric, phosphoric, nitric, carbonic, boric, sulfamic and hydrobromic acids, or salts of pharmaceutically acceptable or compatible organic acids such as acetic, propionic, butyric, tartaric, maleic, hydroxymaleic, fumaric, citric, lactic, mucic, gluconic, benzoic, succinic, oxalic, phenylacetic, methanesulfonic, toluenesulfonic, benzenesulfonic, salicyclic, sulfanilic, aspartic, glutamic, edetic, stearic, palmitic, oleic, lauric, pantothenic, tannic, ascorbic and valeric acids. Base salts include, but are not limited to, those formed with pharmaceutically acceptable or compatible cations, such as sodium, potassium, lithium, calcium, magnesium, ammonium and alkylammonium. Also, basic nitrogen-containing groups may be quatemized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl and diethyl sulfate; and others. However, it will be appreciated that non-pharmaceutically acceptable or compatible salts also fall within the scope of the invention since these may be useful in the preparation of pharmaceutically acceptable or compatible salts. The preparation of salts and prodrugs and derivatives can be carried out by methods known in the art. For example, metal salts can be prepared by reaction of a compound of the invention with a metal hydroxide. An acid salt can be prepared by reacting an appropriate acid with a compound of the invention. [0092] The term "selective" refers to compounds that inhibit PLA2G2A without displaying substantial inhibition towards another PLA ₂ enzyme (e.g., PLA2G1 , PLA2G3, PLA2G5, PLA2G9, PLA2G10, PLA2G 1 1, PLA2G12, PLA2G13 and/or PLA2G 1.4). Accordingly, a compound that is selective for PLA2G2A exhibits a PLA2G2A selectivity of greater than about 2-fold, 5-fold, 10-fold, 20-fold, 50-fold or greater than about 100-fold with respect to inhibition of another PLA ₂ (i.e., a PLA ₂ other than PLA2G2A). In some embodiments, selective compounds display at least 50-fold greater inhibition towards PLA2G2A than towards any one or more of PLA2G1, PLA2G3, PLA2G5, PLA2G9, PLA2G10, PLA2G1 1, PLA2G12, PLA2G13 and PLA2G14. In still other embodiments, selective compounds display at least 100-fold greater inhibition towards PLA2G1, PLA2G3, PLA2G5, PLA2G9, PL A2G 10, PLA2G 1 1 , PLA2G 12, PLA2G 13 and/or PL A2G 14 than towards any one or more of PLA2G1 , PLA2G3, PLA2G5, PLA2G9, PLA2G10, PLA2G1 1, PLA2G12, PLA2G13 and PLA2G14. In still other embodiments, selective compounds display at least 500-fold greater inhibition towards PLA2G2A than towards any one or more of PLA2G 1, PLA2G3, PLA2G5, PLA2G9, PLA2G10, PLA2G1 1 , PLA2G12, PLA2G13 and PLA2G14. In still other embodiments, selective compounds display at least 1000-fold greater inhibition towards PLA2G2A than towards any one or more of PLA2G1, PLA2G3, PLA2G5, PLA2G9, PLA2G10, PLA2G1 1, PLA2G12, PLA2G13 and PLA2G14.

[0093] The term "sequence identity" as used herein refers to the extent that sequences are identical on a nucleotide-by-nucleotide basis or an amino acid-by-amino acid basis over a window of comparison. Thus, a "percentage of sequence identity" is calculated by comparing two optimally aligned sequences over the window of comparison, determining the number of positions at which the identical nucleic acid base (e.g., A, T, C, G, Γ) or the identical amino acid residue {e.g., Ala, Pro, Ser, Thr, Gly, Val, Leu, He, Phe, Tyr, Trp, Lys, Arg, His, Asp, Glu, Asn, Gin, Cys and Met) occurs in both sequences to yield the number of matched positions, dividing the number of matched positions by the total number of positions in the window of comparison (i.e. , the window size), and multiplying the result by 100 to yield the percentage of sequence identity.

[0094] "Similarity" refers to the percentage number of amino acids that are identical or constitute conservative substitutions as defined in Table 1.

TABLE 1

[0095] Similarity may be determined using sequence comparison programs such as GAP (Deveraux et al. 1984, Nucleic Acids Research 12, 387-395). In this way, sequences of a similar or substantially different length to those cited herein might be compared by insertion of gaps into the alignment, such gaps being determined, for example, by the comparison algorithm used by GAP.

[0096] Terms used to describe sequence relationships between two or more polynucleotides or polypeptides include "reference sequence", "comparison window", "sequence identity", "percentage of sequence identity" and "substantial identity". A "reference sequence" is at least 12 but frequently 15 to 18 and often at least 25 monomer units, inclusive of nucleotides and amino acid residues, in length. Because two polynucleotides may each comprise (1) a sequence (i.e., only a portion of the complete polynucleotide sequence) that is similar between the two polynucleotides, and (2) a sequence that is divergent between the two polynucleotides, sequence comparisons between two (or more) polynucleotides are typically performed by comparing sequences of the two polynucleotides over a "comparison window" to identify and compare local regions of sequence similarity. A "comparison window" refers to a conceptual segment of at least 6 contiguous positions, usually about 50 to about 100, more usually about 100 to about 150 in which a sequence is compared to a reference sequence of the same number of contiguous positions after the two sequences are optimally aligned. The comparison window may comprise additions or deletions i.e., gaps) of about 20% or less as compared to the reference sequence (which does not comprise additions or deletions) for optimal alignment of the two sequences. Optimal alignment of sequences for aligning a comparison window may be conducted by computerized implementations of algorithms (GAP,

BESTFIT, FASTA; and TFASTA in the Wisconsin Genetics Software Package Release 7.0, Genetics Computer Group, 575 Science Drive Madison, WI, USA) or by inspection and the best alignment (i.e., resulting in the highest percentage homology over the comparison window) generated by any of the various methods selected. Reference also may be made to the BLAST family of programs as for example disclosed by Altschul et o/.,(Altschul et al, 1997), A detailed discussion of sequence analysis can be found in Unit 1 .3 of Ausubel et al, "Current Protocols in Molecular Biology," John Wiley & Sons Inc. 1994-1998, Chapter 15.

[0097] As used herein a "small molecule" refers to a composition that has a molecular weight of less than 3 kilodaltons (kDa), and typically less than 1.5 kDa, and more preferably less than about 1 kilodalton. Small molecules may be nucleic acids, peptides, polypeptides, peptidomimetics, carbohydrates, lipids or other organic (carbon-containing) or inorganic molecules. As those skilled in the art will appreciate, based on the present description, extensive libraries of chemical and/or biological mixtures, often fungal, bacterial, or algal extracts, may be screened with any of the assays of the invention to identify compounds that modulate a bioactivity. A "small organic molecule" is an organic compound (or organic compound complexed with an inorganic compound (e.g., metal)) that has a molecular weight of less than 3 kDa, less than 1.5 kDa, or even less than about 1 kDa.

[00981 As used herein, "solvate" refers to a crystalline form of a molecule, atom, and/or ions that further contains molecules of a solvent or solvents incorporated into the crystalline structure. The solvent molecules in the solvate may be present in a regular arrangement and/or a non-ordered arrangement. The solvate may comprise either a stoichiometric or nonstoichiometric amount of the solvent molecules. For example, a solvate with a nonstoichiometric amount of solvent molecules may result from partial loss of solvent from the solvate.

[0099J "Stringency" as used herein refers to the temperature and ionic strength conditions, and presence or absence of certain organic solvents, during hybridization. The higher the stringency, the higher will be the observed degree of complementarity between sequences. "Stringent conditions" as used herein refers to temperature and ionic conditions under which only polynucleotides having a high proportion of complementary bases, preferably having exact complementarity, will hybridize. The stringency required is nucleotide sequence dependent and depends upon the various components present during hybridization, and is greatly changed when nucleotide analogues are used. Generally, stringent conditions are selected to be about 10° C to 20° C less than the thermal melting point (Tm) for the Specific sequence at a defined ionic strength and pH. The Tm is the temperature (under defined ionic strength and pH) at which 50% of a target sequence hybridizes to a complementary probe. It will be understood that a polynucleotide will hybridize to a target sequence under at least low stringency conditions, preferably under at least medium stringency conditions and more preferably under high stringency conditions. Reference herein to low stringency conditions include and encompass from at least about 1% v/v to at least about 15% v/v formamide and from at least about 1 M to at least about 2 M salt for hybridization at 42° C, and at least about 1 M to at least about 2 M salt for washing at 42° C. Low stringency conditions also may include 1% Bovine Serum Albumin (BSA), 1 mM EDTA, 0.5 M NaHP04 (pH 7.2), 7% SDS for hybridization at 65° C, and (i) 2xSSC, 0.1 % SDS; or (ii) 0.5% BSA, 1 mM EDTA, 40 mM NaHP04 (pH 7.2), 5% SDS for washing at room temperature. Medium stringency conditions include and encompass from at least about 16% v/v to at least about 30% v/v formamide and from at least about 0.5 M to at least about 0.9 M salt for hybridization at 42° C, and at least about 0.5 M to at least about 0.9 M salt for washing at 42° C. Medium stringency conditions also may include 1% Bovine Serum Albumin (BSA), 1 mM EDTA, 0.5 M NaHP04 (pH 7.2); 7% SDS for hybridization at 65° C, and (i) 2 x SSC, 0.1% SDS; or (ii) 0.5% BSA, 1 mM EDTA, 40 mM NaHP04 (pH 7.2), 5% SDS for washing at 42° C. High stringency conditions include and encompass from at least about 31% v/v to at least about 50% v/v formamide and from at least about 0.01 M to at least about 0.15 M salt for hybridization at 42° C, and at least about 0.01 M to at least about 0.15 M salt for washing at 42° C. High stringency conditions also may include 1% BSA, 1 mM EDTA, 0.5 M NaHP04 (pH 7.2), 7% SDS for hybridization at 65° C, and (i) 0.2 x SSC, 0.1% SDS; or (ii) 0.5% BSA, ImM EDTA, 40 mM NaHP04 (pH 7.2), 1% SDS for washing at a temperature in excess of 65° C. One embodiment of high stringency conditions includes hybridizing in 6 x SSC at about 45° C, followed by one or more washes in 0.2 x SSC, 0.1% SDS at 65° C. One embodiment of very high stringency conditions includes hybridizing 0.5 M sodium phosphate, 7% SDS at 65° C, followed by one or more washes at 0.2 x SSC, 1% SDS at 65° C. Other stringent conditions are well known in the art. A skilled addressee will recognize that various factors can be manipulated to optimize the specificity of the hybridization. Optimization of the stringency of the final washes can serve to ensure a high degree of hybridization. For detailed examples, see CURRENT PROTOCOLS IN

MOLECULAR BIOLOGY (supra) at pages 2.10.1 to 2.10.16 and MOLECULAR CLONING. A LABORATORY MANUAL (Sambrook, et al, eds.) (Cold Spring Harbor Press 1989) at sections 1.101 to 1.104. [0101] As used herein, the terms "treatment", "treating", and the like, refer to obtaining a desired pharmacologic and/or physiologic effect. The effect may be prophylactic in terms of completely or partially preventing a disease or symptom thereof and/or may be therapeutic in terms of a partial or complete cure for a disease and/or adverse affect attributable to the disease. "Treatment", as used herein, covers any treatment of a disease in a mammal, particularly in a human, and includes: (a) preventing the disease from occurring in a subject which may be predisposed to the disease but has not yet been diagnosed as having it; (b) inhibiting the disease, i.e., arresting its development; and (c) relieving the disease, i.e., causing regression of the disease.

|0102] "Type II diabetes" or "non-insulin dependent diabetes mellitus" refers to an insulin-related disorder in which there is a relative disparity between endogenous insulin production and insulin requirements, leading to elevated hepatic glucose production, elevated blood glucose levels, inappropriate insulin secretion, and peripheral insulin resistance. Type II diabetes has been regarded as a relatively distinct disease entity, but type II diabetes is often a manifestation of a much broader underlying disorder (Zimmet et al, 2001 Nature 414: 782-787), which may include metabolic syndrome (syndrome X), diabetes {e.g., type II diabetes, type II diabetes, gestational diabetes, autoimmune diabetes), hyperinsulinemia, hyperglycemia, impaired glucose tolerance (IGT), hypoglycemia, B-cell failure, insulin resistance, dyslipidemias, atheroma, insulinoma, hypertension, hypercoagulability, microalbuminuria, and obesity and other adiposity-related conditions such as visceral obesity, central fat, obesity-related type II diabetes, obesity-related atherosclerosis, heart disease, obesity-related insulin resistance, obesity-related hypertension, microangiopathic lesions resulting from obesity-related type II diabetes, ocular lesions caused by microangiopathy in obese individuals with obesity-related type U diabetes, and renal lesions caused by microangiopathy in obese individuals with obesity-related type II diabetes.

(0103] By "vector" is meant a polynucleotide molecule, suitably a DNA molecule derived, for example, from a plasmid, bacteriophage, yeast or virus, into which a polynucleotide can be inserted or cloned. A vector may contain one or more unique restriction sites and can be capable of autonomous replication in a defined host cell including a target cell or tissue or a progenitor cell or tissue thereof, or be integrable with the genome of the defined host such that the cloned sequence is reproducible. Accordingly, the vector can be an autonomously replicating vector, i.e., a vector that exists as an extra-chromosomal entity, the replication of which is independent of chromosomal replication, e.g., a linear or closed circular plasmid, an extra-chromosomal element, a mini- chromosome, or an artificial chromosome. The vector can contain any means for assuring self- replication. Alternatively, the vector can be one which, when introduced into the host cell, is integrated into the genome and replicated together with the chromosome(s) into which it has been integrated. A vector system can comprise a single vector or plasmid, two or more vectors or plasmids, which together contain the total DNA to be introduced into the genome of the host cell, or a transposon. The choice of the vector will typically depend on the compatibility of the vector with the host cell into which the vector is to be introduced. In the present case, the vector is preferably a viral or viral-derived vector, which is operably functional in animal and preferably mammalian cells. Such vector may be derived from a poxvirus, an adenovirus or yeast. The vector can also include a selection marker such as an antibiotic resistance gene that can be used for selection of suitable transformants. Examples of such resistance genes are known to those of skill in the art and include the «ρί/T gene that confers resistance to the antibiotics kanamycin and G418 (Geneticin®) and the hph gene which confers resistance to the antibiotic hygromycin B.

[0104] The terms "wild-type" and "naturally occurring" are used interchangeably to refer to a gene or gene product that has the characteristics of that gene or gene product when isolated from a naturally occurring source. A wild type gene or gene product (e.g., a polypeptide) is that which is most frequently observed in a population and is thus arbitrarily designed the "normal" or "wild-type" form of the gene.

[0105] As used herein, underscoring or italicizing the name of a gene shall indicate the gene, in contrast to its protein product, which is indicated by the name of the gene in the absence of any underscoring or italicizing. For example, "PLA2G2A" shall mean the PLA2G2A gene or

PLA2G2A polynucleotides, whereas "PLA2G2A" shall indicate the protein product or products generated from transcription and translation and alternative splicing of the "PLA2G2A" gene.

2. Abbreviations

[0106 The following abbreviations are used throughout the application:

PLA = phospholipase

P.O. per oral treatment by oral gavage

ppara = peroxisome proliferator-activator receptor

s = seconds

srebf = sterol regulatory element binding transcription factor

SVC = stromal vascular cells

ucp = uncoupling protein

3. PLA2G2A inhibitors for use in treating or preventing adiposity-related conditions

[0107] The present invention provides PLA2G2A inhibitors in methods and compositions for controlling adiposity in a subject including adiposity related conditions such as obesity, conditions of localized, abnormal increases in adiposity. When included in compositions, the PLA2G2A inhibitors are .suitably combined with a pharmaceutically acceptable carrier. Conditions contemplated in such treatment regimes include conditions or pathologies which are associated with or secondary to obesity, such but not limited to type II diabetes, overeating, binge eating, and bulimia, hypertension, elevated plasma insulin concentrations and insulin resistance, dyslipidemia, hyperlipidemia, obstructive sleep apnea, heart disease, abnormal heart rhythms and arrhythmias, myocardial infarction, congestive heart failure, coronary heart disease, sudden death, stroke and other pathological conditions showing reduced metabolic activity or a decrease in resting energy expenditure as a percentage of total fat-free mass, e.g., children with acute lymphoblastic leukemia. Further examples of adiposity-related conditions are metabolic syndrome, insulin resistance syndrome, reproductive hormone abnormalities, sexual and reproductive dysfunction, such as impaired fertility, infertility, hypogonadism in males and hirsutism in females, fetal defects associated with maternal obesity, gastrointestinal motility disorders, such as obesity-related gastro-esophageal reflux, respiratory disorders, such as obesity-hypoventilation syndrome (Pickwickian syndrome), breathlessness, cardiovascular disorders, inflammation, such as systemic inflammation of the vasculature, arteriosclerosis, hypercholesterolemia, lower back pain, gallbladder disease, hyperuricemia, gout, and kidney cancer, and increased anesthetic risk. Conditions of localized, abnormal increases in adiposity may include adipose tumors (lipomas and liposarcomas) and lipomatosis. In specific embodiments, the adiposity related condition is selected from obesity, type II diabetes and metabolic syndrome.

[0108] The PLA2G2A inhibitors can be administered by any suitable route including for example by injection, by topical or mucosal application, by inhalation or via the oral route including modified-release modes of administration to control excess adiposity and/or to treat or prevent an adiposity-related condition in a subject.

[0109] PLA2G2A inhibitors include and encompass any active compound that binds to" a PLA2G2A polypeptide and that suitably inhibits the functional activity of the PLA2G2A or reduce the expression of the PLA2G2A gene, including nucleic acids, peptides, polypeptides, peptidomimetics or other organic (carbon containing) or inorganic molecules. Suitable PLA2G2A inhibitors include nucleic acids such as antisense molecules, siR A and shRNA, amino acid inhibitors, aptamers, peptides as well as small molecule organic inhibitors of PLA2G2A.

3.1 PLA2G2A nucleic acid inhibitors

[0110] The present invention encompasses any inhibitors that reduce or abrogate

PLA2G2A gene expression in immune cells that infiltrate, are contained in or are otherwise associated with adipose tissue. Non-limiting agents of this type include nucleic acid molecules that function to inhibit transcription of PLA2G2A genes or translation of encoded transcripts including PLA2G2A mRNA. Representative nucleic acid molecules of this type include:

[0111] nucleotide sequences selected from the group consisting of:

[0112] gagtcagtgtcagcccgaaggctgaaggaaaaagagcaacagatccagggagcattcacc tgccctgtctccaaaca gccttgtgcctcacctacccccaacctcccagagggagcagctatttaaggggagcagga gtgcagaacaaacaagacggcctggggatacaac tctggagtcctctgagagagccaccaaggaggagcaggggagcgacggccggggcagaag ttgagaccacccagcagaggagctaggccag tccatctgcatttgtcacccaagaactcttaccatgaagaccctcctactgttggcagtg atcatgatctttggcctactgcaggcccatgggaatttggt gaatttccacagaatgatcaagttgacgacaggaaaggaagccgcactcagttatggctt ctacggctgccactgtggcgtgggtggcagaggatc ccccaaggatgcaacggatcgctgctgtgtcactcatgactgttgctacaaacgtctgga gaaacgtggatgtggcaccaaatttctgagctacaagt ttagcaactcggggagcagaatcacctgtgcaaaacaggactcctgcagaagtcaactgt gtgagtgtgataaggctgctgccacctgttttgctaga aacaagacgacctacaataaaaagtaccagtactattccaataaacactgcagagggagc acccctcgttgctgagtcccctcttccctggaaacctt ccacccagtgctgaatttccctctctcataccctccctccctaccctaaccaagttcctt ggccatgcagaaagcatccctcacccatcctagaggcca ggcaggagcccttctatacccacccagaatgagacatccagcagatttccagccttctac tgctctcctccacctcaactccgtgcttaaccaaagaa gctgtactccggggggtctcttctgaataaagcaattagcaaatcatgtaaaaaaaaaaa aaaaaaa [SEQ ID NO: 1 ; PLA2G2A transcript variant 1];

[0113] gagtcagtgtcagcccgaaggctgaaggaaaaagagcaacagatccagggagcattcacc tgccctgtctccaaaca gagggagcagctatttaaggggagcaggagtgcagaacaaacaagacggcctggggatac aactctggagtcctctgagagagccaccaagga ggagcaggggagcgacggccggggcagaagttgagaccacccagcagaggagctaggcca gtccatctgcatttgtcacccaagaactcttac catgaagaccctcctactgttggcagigatcatgatctttggcctactgcaggcccatgg gaatttggtgaatttccacagaatgatcaagttgacgac aggaaaggaagccgcactcagttatggcttctacggctgccactgtggcgtgggtggcag aggatcccccaaggatgcaacggatcgctgctgtg tcactcatgactgttgctacaaacgictggagaaacgiggatgtggcaccaaatttctga gctacaagtttagcaactcggggagcagaatcacctgt gcaaaacaggactcctgcagaagtcaactgtgtgagtgtgataaggctgctgccacctgt tttgctagaaacaagacgacctacaataaaaagtacc agtactattccaataaacactgcagagggagcacccctcgttgctgagtcccctcttccc tggaaaccttccacccagtgctgaatttccctctctcata ccctccctccctaccctaaccaagttccttggccatgcagaaagcatccctcacccatcc tagaggccaggcaggagcccttctatacccacccaga atgagacatccagcagatttccagccttctactgctctcctccacctcaactccgtgctt aaccaaagaagctgtactccggggggtctcttctgaataa agcaattagcaaatcatgtaaaaaaaaaaaaaaaaaa [SEQ ID NO:2; PLA2G2A transcript variant 2];

[0114] gagtcagtgtcagcccgaaggctgaaggaaaaagagcaacagatccagggagcattcacc tgccctgtctccaaaca gagccaccaaggaggagcaggggagcgacggccggggcagaagttgagaccacccagcag aggagctaggccagtccatctgcatttgtcac ccaagaactcttaccatgaagaccctcctactgttggcagtgatcatgatctttggccta ctgcaggcccatgggaatttggtgaatttccacagaatga tcaagttgacgacaggaaaggaagccgcactcagttatggcttctacggctgccactgtg gcgtgggtggcagaggatcccccaaggatgcaacg gatcgctgctgtgtcactcatgactgttgctacaaacgtctggagaaacgtggatgtggc accaaatttctgagctacaagtttagcaactcggggag cagaatcacctgtgcaaaacaggactcctgcagaagtcaactgtgigagtgtgataaggc tgctgccacctgttttgctagaaacaagacgacctac aataaaaagtaccagtactattccaataaacactgcagagggagcacccctcgttgctga gtcccctcttccctggaaaccttccacccagtgctgaa tttccctctctcataccctccctccctaccctaaccaagttccttggccatgcagaaagc atccctcacccatcctagaggccaggcaggagcccttct atacccacccagaatgagacatccagcagatttccagccttctactgctctcctccacct caactccgtgcttaaccaaagaagctgtactccggggg gtctcttctgaataaagcaattagcaaatcatgtaaaaaaaaaaaaaaaaaa [SEQ ID N0:3; PLA2G2A transcript variant 3];

[0115] agggagcagctatttaaggggagcaggagtgcagaacaaacaagacggcctggggataca actctggagtcctctg agaggttggatgggagagcatgtctgtgtgtctcagagccaccaaggaggagcaggggag cgacggccggggcagaagttgagaccacccag cagaggagctaggccagtccatctgcatttgtcacccaagaactcttaccatgaagaccc tcctactgttggcagtgatcatgatctttggcctactgc aggcccatgggaamggtgaatttccacagaatgatcaagttgacgacaggaaaggaagcc gcactcagttatggcttctacggctgccactgtgg cgtgggtggcagaggatcccccaaggatgcaacggatcgctgctgtgtcactcatgactg ttgctacaaacgtctggagaaacgtggatgtggcac caaatttctgagctacaagtttageaactcggggagcagaatcacctgtgcaaaacagga ctcctgcagaagtcaactgtgtgagtgtgataaggct gctgccacctgttttgctagaaacaagacgacctacaataaaaagtaccagtactattcc aataaacactgcagagggagcacccctcgttgctgagt cccctcttccctggaaaccttccacccagtgctgaatttccctctctcataccctccctc cctaccctaaccaagttccttggccatgcagaaagcatcc ctcacccatcctagaggccaggcaggagcccttctatacccacccagaatgagacatcca gcagatttccagccttctactgctctcctccacctcaa ctccgtgcttaaccaaagaagctgtactccggggggtctcttctgaataaagcaattagc aaatcatgtaaaaaaaaaaaaaaaaaa [SEQ ID N0:4; PLA2G2A transcript variant 4];

[0116J nucleotide sequences that share at least 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99% sequence identity with any one of SEQ ID NOi l to 4;

[0117] nucleotide sequences that hybridize under at least low, medium or high stringency conditions to any one of SEQ ID NO: 1 to 4;

[0118] nucleotide sequences that encode the amino acid sequence:

[0119] M TLLLLAVIMIFGLLQAHGNLV FHRMIKLTTG EAALSYGFYGCHCGV

GGRGSP DATDRCCVTHDCCYKRLEKRGCGTKFLSY FSNSGSRITCAKQDSCRSQLCECDK AAATCFARN TTYNKKYQYYSNKHCRGSTPRC [SEQ ID NO:5; PLA2G2A];

[0120] nucleotide sequences that encode an amino acid sequence that shares at least 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99% sequence similarity with SEQ ID NO:5; and

[0121] nucleotide sequences that encode an amino acid sequence that shares at least 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99% sequence identity with SEQ ID NO:5. [0122] Illustrative nucleic acid inhibitor molecules include antisense molecules, aptamers, ribozymes and triplex forming molecules, R Ai and external guide sequences. The nucleic acid molecules can act as effectors, inhibitors, modulators, and stimulators of a specific activity possessed by a target molecule, or the functional nucleic acid molecules can possess a de novo activity independent of any other molecules.

[0123] Inhibitor nucleic acid molecules can interact with any macromolecule, such as DNA, RNA, polypeptides, or carbohydrate chains. Thus, inhibitor nucleic acid molecules can interact with PLA2G2A mR A or the genomic DNA of PL2G2A or they can interact with the PLA2G2A polypeptide. Often inhibitor nucleic acid molecules are designed to interact with other nucleic acids based on sequence homology between the target molecule and the inhibitor nucleic acid molecule. In other situations, the specific recognition between the inhibitor nucleic acid molecule and the target molecule is not based on sequence homology between the inhibitor nucleic acid molecule and the target molecule, but rather is based on the formation of tertiary structure that allows specific recognition to take place.

[0124] In some embodiments, anti-sense RNA or DNA molecules are used to directly block the translation of PLA2G2A mRNA by binding to targeted mRNA and preventing protein translation. Antisense molecules are designed, to interact with a target nucleic acid molecule through either canonical or non-canonical base pairing. The interaction of the antisense molecule and the target molecule may be designed to promote the destruction of the target molecule through, for example, RNAseH mediated RNA-DNA hybrid degradation. Alternatively the antisense molecule may be designed to interrupt a processing function that normally would take place on the target molecule, such as transcription or replication. Antisense molecules can be designed based on the sequence of the target molecule. Numerous methods for optimization of antisense efficiency by finding the most accessible regions of the target molecule exist. Non-limiting methods include in vitro selection experiments and DNA modification studies using DMS and DEPC. Suitably, the antisense molecules bind the target molecule with a dissociation constant (Kd) less than or equal to 10 ^"6 , 10 ^" \ 10 ^"10 , or 10 ^{' n} . In specific embodiments, antisense oligodeoxyribonucleotides derived from the translation initiation site, e.g., between -10 and +10 regions are employed. Non-limiting antisense molecules are described for example by Lappas et al. (Lappas et al, 2001) and Barbour et al (Barbour and Dennis, 1993). In illustrative examples, PLA2G2A antisense molecules comprise, consist or consist essentially of a nucleotide sequence selected from:

[0125] 5 -GGGTGGGTATAGAAGGGCTCC-3' [SEQ ID NO: 6];

[0126] 5'-TTTTTG ATTTGCT A ATTGCTT-3 ' [SEQ ID NO:7]; and

[0127] 5'-GATCCTCTGCCACCCACACC-3' [SEQ ID NO:8]. [0128] Aptamers are molecules that interact with a target molecule, suitably in a specific way. Aptamers are generally small nucleic acids ranging from 15-50 bases in length that fold into defined secondary and tertiary structures, such as stem-loops or G-quartets. Aptamers can bind small molecules, such as ATP and theophiline, as well as large molecules, such as reverse transcriptase and thrombin. Aptamers can bind very tightly with fas from the target molecule of less than 10 ^"12 M. Suitably, the aptamers bind the target molecule with a fa less than 10 ^"6 , 10 ^'8 , 10 ^'10 or 10 ^'12 . Aptamers can bind the target molecule with a very high degree of specificity. For example, aptamers have been isolated that have greater than a 10,000 fold difference in binding affinities between the target molecule and another molecule that differ at only a single position on the molecule. It is desirable that an aptamer have a fa with the target molecule at least 10-, 100-, 1000-, 10,000-, or 100,000-fold lower than the fa with a background-binding molecule. Non-limiting PLA2G2A aptamers are described for example by Bridonneau et al. (Bridonneau et al., 1998), illustrative examples of which comprise, consist or consist essentially of a nucleotide sequence selected from:

10129] aagaCGGCCGGGGAAACCCGAGGUCCGAGGUAACGC [SEQ ID NO:?]; (0130] aagaCGGCCGGGGAAACCCGAGGUCCGAUGUAACGC [SEQ ID NO.10];

[0131] aagaCGGCCGGGGAAACCCGAGAUCCGAGGUAACGC [SEQ ID NO: 1 1 ];

[0132] aagaCGGCCGGCGCCAUAGCCGAGAUCCGAGGUUGUAC [SEQ ID NO: 12];

[0133] aagaCGGCCGGCGCCAUAGCCGAGAUCCGAGGUGUUGA [SEQ ID NO: 13];

[0134] gaGACGGCCAGCCAAGGCGCUGAGAUCCGAGGUUUCAG [SEQ ID NO: 14];

[0135] aagaCGGCCCGGUAUGUAGCCGGAGAUCCGAGACUUGCU [SEQ ID

NO: 15];

[0136] aagaCGGCCCGGUGUGUAGCCGGAGAUCCGAGACUUGCU [SEQ ID

NO: 16];

[0137] aagaCGGCCCGGUGUGCAGCCGGAGAUCCGAGACUUGCU [SEQ ID

NO: 17]; and

[0138] aagaCGGCCCCGCCAAUCAAGGGAGAUCCGAGGAAUUGG [SEQ ID

NO: 18].

[0139] In other embodiments, &nt\-PLA2G2A ribozymes are used for catalyzing the specific cleavage of PLA2G2A RNA. The mechanism of ribozyme action involves sequence Specific hybridization of the ribozyme molecule to complementary target RNA, followed by a endonucleolytic cleavage. There are several different types of ribozymes that catalyze nuclease or nucleic acid polymerase type reactions, which are based on ribozymes found in natural systems, such as hammerhead ribozymes, hairpin ribozymes, and tetrahymena ribozymes. There are also a number of ribozymes that are not found in natural systems, but which have been engineered to catalyze specific reactions de novo. Representative ribozymes cleave RNA or DNA substrates. In some embodiments, ribozymes that cleave RNA substrates are employed. Specific ribozyme cleavage sites within potential RNA targets are initially identified by scanning the target molecule for ribozyme cleavage sites, which include the following sequences, GUA, GUU and GUC. Once identified, short RNA sequences of between 15 and 20 ribonucleotides corresponding to the region of the target gene containing the cleavage site may be evaluated for predicted structural features such as secondary structure that may render the oligonucleotide sequence unsuitable. The suitability of candidate targets may also be evaluated by testing their accessibility to hybridization with complementary oligonucleotides, using ribonuclease protection assays.

[0140] Triplex forming functional nucleic acid molecules are molecules that can interact with either double-stranded or single-stranded nucleic acid. When triplex molecules interact with a target region, a structure called a triplex is formed, in which there are three strands of DNA forming a complex dependent on both Watson-Crick and Hoogsteen base pairing. Triplex molecules are preferred because they can bind target regions with high affinity and specificity. It is generally desirable that the triplex forming molecules bind the target molecule with a Κ _Λ less than 10 ^" *, 10 ^'8 , 10 ^{' ,c} , or l0- ¹² .

[0141] External guide sequences (EGSs) are molecules that bind a target nucleic acid molecule forming a complex, and this complex is recognized by RNAse P, which cleaves the target molecule. EGSs can be designed to specifically target a RNA molecule of choice. RNAse P aids in, processing transfer RNA (tRNA) within a cell. Bacterial RNAse P can be recruited to cleave virtually any RNA sequence by using an EGS that causes the target RNA:EGS complex to mimic the natural tRNA substrate. Similarly, eukaryotic EGS RNAse P-directed cleavage of RNA can be utilized to cleave desired targets within eukaryotic cells.

[0142] In other embodiments, RNA molecules that mediate RNA interference (RNAi) of a PLA2G2A gene or PLA2G2A transcript can be used to reduce or abrogate gene expression. RNAi refers to interference with or destruction of the product of a target gene by introducing a single- stranded or usually a double-stranded RNA (dsRNA) that is homologous to the transcript of a target gene. RNAi methods, including double-stranded RNA interference (dsRNAi) or small interfering RNA (siRNA), have been extensively documented in a number of organisms, including mammalian cells and the nematode C. elegans (Fire et al, 1998). In mammalian cells, RNAi can be triggered by 21- to 23-nucIeotide (nt) duplexes of small interfering RNA (siRNA) (Chiu and Rana, 2002; Elbashir et al, 2001 ), or by micro-RNAs (miRNA), functional small-hairpin RNA (shRNA), or other dsRNAs which are expressed in vivo using DNA templates with RNA polymerase III promoters (Lee et al, 2002; McManus et al., 2002; Paddison et al, 2002; Paul et al, 2002; Sui et al, 2002; Tuschl, 2002; Yu et al, 2002; Zeng et al, 2002).

[0143] In specific embodiments, dsRNA per se and especially dsRNA-producing constructs corresponding to at least a portion of a PLA2G2A gene are used to reduce or abrogate its expression. RNAi-mediated inhibition of gene expression may be accomplished using any of the techniques reported in the art, for instance by transfecting a nucleic acid construct encoding a stem- loop or hairpin RNA structure into the genome of the target cell, or by expressing a transfected nucleic acid construct having homology for a PLA2G2A gene from between convergent promoters, or as a head to head or tail to tail duplication from behind a single promoter. Any similar construct may be used so long as it produces a single RNA having the ability to fold back on itself and produce a dsRNA, or so long as it produces two separate RNA transcripts, which then anneal to form a dsRNA having homology to a target gene.

[0144] Absolute homology is not required for RNAi, with a lower threshold being described at about 85% homology for a dsRNA of about 200 base pairs (Plasterk and Ketting, 2000). Therefore, depending on the length of the dsRNA, the RNAi-encoding nucleic acids can vary in the level of homology they contain toward the target gene transcript, i.e., with dsR As of 100 to 200 base pairs having at least about 85% sequence identity with the target gene, and longer dsRNAs, i.e., 300 to 100 base pairs, having at least about 75% sequence identity to the target gene. RNA-encoding constructs that express a single RNA transcript designed to anneal to a separately expressed RNA, or single constructs expressing separate transcripts from convergent promoters, are suitably at least about 100 nucleotides in length. RNA-encoding constructs that express a single RNA designed to form a dsRNA via internal. folding are usually at least about 200 nucleotides in length.

[0145] The promoter used to express the dsRNA-forming construct may be any type of promoter if the resulting dsRNA is specific for a gene product in the cell lineage targeted for destruction. Alternatively, the promoter may be lineage specific in that it is only expressed in cells of a particular development lineage. This might be advantageous where some overlap in homology is observed with a gene that is expressed in a non-targeted cell lineage. The promoter may also be inducible by externally controlled factors, or by intracellular environmental factors.

[0146] In some embodiments, RNA molecules of about 21 to about 23 nucleotides, which direct cleavage of specific mRNA to which they correspond, as for example described by Tuschl et al. in U.S. Patent Application Publication No. 20020086356, can be utilized for mediating RNAi. Such 21- to 23-nt RNA molecules can comprise a 3' hydroxyl group, can be single-stranded or double stranded (as two 21- to 23-nt RNAs) wherein the dsRNA molecules can be blunt ended or comprise overhanging ends (e.g., 5', 3'). [0147] In some embodiments, the inhibitor nucleic acid molecule is a siRNA. siRNAs can be prepared by any suitable method. For example, reference may be made to International Publication WO 02/44321, which discloses siRNAs capable of sequence-specific degradation of target mRNAs when base-paired with 3' overhanging ends, which is incorporated by reference herein. Sequence specific gene silencing can be achieved in mammalian cells using synthetic, short double-stranded RNAs that mimic the siRNAs produced by the enzyme dicer. siRNA can be chemically or in vitro- synthesized or can be the result of short double-stranded hairpin-like RNAs (shRNAs) that are processed into siRNAs inside the cell. Synthetic siRNAs are generally designed using algorithms and a conventional DNA/RNA synthesizer. Suppliers include Ambion (Austin, Tex.), ChemGenes (Ashland, Mass.), Dharmacon (Lafayette, Colo.), Glen Research (Sterling, Va.), MWB Biotech (Esbersberg, Germany), Proligo (Boulder, Colo.), OriGene (Rockville, MD), Sigma Aldrich (St.

Louis, MO) and Q1AGEN (Hilden, Germany). siRNA can also be synthesized in vitro using kits such as Ambion's SILENCER™ siRNA Construction Kit.

[0148] The production of siRNA from a vector is more commonly done through the transcription of a short hairpin RNAs (shRNAs). Kits for the production of vectors comprising shRNA are available such as for example, Imgenex's GENESUPPRESSOR™ Construction Kits and

Invitrogen's BLOCK-IT™ inducible RNAi plasmid and Ientivirus vectors.

[0149] Illustrative RNAi molecules (e.g. , PLA2G2A siRNA and shRNA) are available commercially from Santa Cruz Biotechnology, Inc., (Santa Cruz, CA, USA) and OriGene

Technologies, Inc. (Rockville, MD) and QIAGEN (Hilden, Germany).

[0150], In specific embodiments, the PLA2G2A nucleic acid inhibitor is a selective PLA2G2A nucleic acid inhibitor.

3.2 PLA2G2A antibody inhibitors

[0151] The present invention also contemplates the use of antibodies that bind to a PLA2G2A polypeptide produced by an immune cell that infiltrates, is contained in or is otherwise i associated with adipose tissue for eliciting at least one of activity selected from: (1) reducing total body mass, (2) reducing adipose tissue inflammation; (3) reducing insulin intolerance or resistance, (4) reducing glucose intolerance, (5) reducing or inhibiting elevation of macrophage numbers infiltrating into adipose tissue, (6) reducing PGE ₂ levels in adipose tissue, (7) preventing cardiovascular abnormalities such as cardiac fibrosis and remodeling in the heart, (8) reducing PGE ₂ release from adipose immune cells, (9) protecting against diet-induced metabolic syndrome, or (10) controlling adiposity including in the treatment or prevention of adiposity-related conditions.

[0152] Representative antibodies include whole antibodies (e.g., polyclonal or monoclonal) that bind to a PLA2G2A polypeptide. The invention also contemplates antibody fragments including Fv, Fab, Fab' and F(ab')2 immunoglobulin fragments. Alternatively, the antibody may be in the form of a synthetic stabilized Fv fragment, a single variable region domain (also known as a dAbs), a "minibody" and the like as known in the art. Antibodies also encompass dimeric antibodies, as well as multivalent forms of antibodies.

[0153] In some embodiments, the PLA2G2A antibodies are chimeric antibodies in which a portion of the heavy and/or light chain is identical with or homologous to corresponding sequences in antibodies derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is identical with or homologous to corresponding sequences in antibodies derived from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies, so long as they exhibit the desired biological activity (see, for example, U.S. Pat. No. 4,816,567; and Morrison et al. (Morrison et al, 1984)).

[0154] Also contemplated as antibodies are humanized antibodies. Humanized antibodies are produced by transferring complementary determining regions from heavy and light variable chains of a non human (e.g., rodent, suitably mouse) immunoglobulin into a human variable domain. Typical residues of human antibodies are then substituted in the framework regions of the non human counterparts. The use of antibody components derived from humanized antibodies obviates potential problems associated with the immunogenicity of non human constant regions. General techniques for cloning non human, particularly murine, immunoglobulin variable domains are described, for example, by Orlandi et al. (Orlandi et al, 1989). Techniques for producing humanized monoclonal antibodies are described, for example, by Jones. et al. (Jones et al, 1986), Carter et al. (Carter et al, 1992), Sandhu (Sandhu, 1992), Singer et al (Singer et al, 1993), Sudhir (ed., Antibody Engineering Protocols, Humana Press, Inc. 1995), Kelley ("Engineering Therapeutic Antibodies," in Protein Engineering: Principles and Practice Cleland et al. (eds.), pages 399-434 (John Wiley & Sons, Inc. 1996), and by Queen e/ fl/., U.S. Pat. No. 5,693,762.

[0155] For example, numerous anti-PLA2G2A antibodies are known, illustrative examples of which are disclosed by Landes et al. in U.S. Pat. Appl. Pub. No. 2005/0058649, which is expressly incorporated herein by reference in its entirety. A range of PLA2G2A antibodies is available commercially, for example, the PLA2G2A antibodies sc- 14467 and sc-20105 (Santa Cruz

Biotechnology, Inc., Santa Cruz, CA, USA), SCACC353 (Abeam, Cambridge, UK) and human PLA2G2A MAb (Clone 620501) (R&D Systems, San Francisco, USA).

[0156] In specific embodiments, the anti-PLA2G2A antibody is a selective PLA2G2A inhibitor.

3.3 PLA2G2A peptide inhibitors

[0157] The present invention also contemplates peptide compounds that inhibit the functional activity of a PLA2G2A polypeptide. For example, non-limiting peptide inhibitors of PLA2G2A are disclosed by Thwin et al. (Thwin et al., 2007), which include compounds that comprise, consist or consist essentially of the amino acid sequence:

[0158] LGRVDIHVWDGVYIRGR [SEQ ID NG: 19];

(0159) LGRVDEHVWDGVYIRG [SEQ ID NO:20];

[0160] LGRVDIHVWDGVYIR [SEQ ID NO:21];

[0161] LGRVDIHVWDGVYI [SEQ ID NO:22];

[0162] LGRVDIHVWDGVY [SEQ ID NO:23];

[0163] RVDIHVWDGV [SEQ ID NO:24];

[0164] VDIHVWDGV [SEQ ID NO:25];

[0165] DMVWDGV [SEQ ID NO:26];

[0166] IHVWDGV [SEQ ID NO:27];

[0167] VDIHVWDGV; ^v

[0168] VDIHVWAGV

[0169] VDIHVWEGV

[0170] VDIHVWSGV; and

[0171] VDIHV WDG V-VDHTV WDGV .

[0172] In specific embodiments, the PLA2G2A peptide inhibitor is a selective PLA2G2A peptide inhibitor.

3.4 PLA2G2A small molecule inhibitors

[0173] The present invention also contemplates small molecule inhibitors of PLA2G2A

(suitably PLA2G2A selective inhibitors) for use in the methods and compositions disclosed herein. In some embodiments, the small molecule inhibitors are selected from D-amino acid derivative compounds as described for example in U.S. Pat. No. 7,253, 194 (Reid), which is expressly incorporated herein by reference in its entirety. In some embodiments, these compounds are represented by formula (I):

[0174]

[0175] wherein: [0176J X is selected from the group consisting of:

[0177] CRR'C0 ₂ H, CRR'-tetrazolyl, CRR ^* S0 ₃ H, CRR' P(0)(OH)2, CRR' P(0)(OH)(OR"), CHRCH ₂ C0 ₂ H, CHRCH ₂ -tetrazo]yl, CHRCH ₂ S0 ₃ H, CHRCH2p(0)(OH)2, CHRCH2P(0)(OH)(OR"), OP(0)(OH)R', NRSO3H, NRP(0)(OH) ₂ , NRP(0)(OHXOR")

[0178) wherein R, R' and R" are independently selected from hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted acyl, optionally substituted arylalkyl, optionally substituted cycloalkylalkyl and optionally substituted heterocyclylalkyl, except that R" is not hydrogen;

[0179] Q is a group selected from formulae (a)-(g):

[01

(b) (c)

(d) .(e) (f) (g)

[0181] Y and Z are independently a group selected from formulae (i)-(iv):

[0182] (i) -(CH2) _m -aa-(CH ₂ )„-B; or

[0183] (ii) -(CH ₂ ) _m -aa-(CH2)„-A-(CH2) ₀ -B; or

[0184] (iii) -(CH ₂ ) _p -A-(CH2) _q -A'-(CH2) _r -B; or

[0185] (iv) -(CH ₂ ) ₈ -B;

[0186] wherein

[0187] m is 0 or 1 , n, 0, p, q and r are independently selected from 0 to 15 and s is from 5 to 15,

[0188] aa is an amino acid side chain residue; [0189) A and A' are independently selected from O, S, NH, NR, NHC(O), NRC(O), CH ₂ , CHR, CHNH ₂ , C(O), C(0)0, C(0)NH, OC(O), and CH=CH, wherein R is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted arylalkyl, optionally substituted cycloalkylalkyl and optionally substituted heterocyclylalkyl; and

[01901 B ' ^s selected from, hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted cycloalkyl, optionally substituted aryloxy, and optionally substituted heterocyclyloxy; optionally substituted cycloalkyloxy, CO2H; and

[0191] wherein m, n, o, p, q, r, s, aa, A, A' and B are such that the longest continuous chain of atoms in a group of formula (i)-(iv) is from 5 to 15 atoms long;

[0192] or salt, derivative or prodrug thereof.

[0193] In some embodiments, the compound is a compound of formula (IC):

[0194] (IC)

[0195] wherein:

[0196] X is selected from the group consisting of:

[0197] CRR'C0 ₂ H, CRR'-tetrazolyl, CRR'S0 ₃ H, CRR' P(0)(OH) ₂ , CRR' P(0)(OH)(OR"), CHRCH ₂ C0 ₂ H, CHRCHrtetrazolyl, CHRCH ₂ S0 ₃ H, CHRCH ₂ P(0)(OH) ₂ , CHRCH ₂ P(0)(OH)(OR"), OP(0)(OH)R', NRSO3H, NRP(0)(OH) _2> NRP(0)(OHXOR")

[0198] wherein R, R' and R" are independently selected from hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted acyl, optionally substituted arylalkyl, optionally substituted cycloalkylalkyl and optionally substituted heterocyclylalkyl, except that R" is not hydrogen;

[0199] Q is a group selected from formulae (a)-(g): [02

(a) (b) (c)

(d) (e) (f) (g)

[0201] Y and Z are independently a group selected from formulae (i)-(iv):

[0202] (i) -(CH ₂ ) _m -aa-(CH ₂ ) _n -B; or

[0203] (ii) -(CH ₂ ) _m -aa-(CH2) _n -A-(CH ₂ ) ₀ -B; or

[0204] (iii) -(CH ₂ ) _p -A CH ₂ ),pV-(CH ₂ ) _r -B; or

[0205] (iv) -(CH ₂ ) _S -B;

[0206] wherein

[0207] m is 0 or 1, n, o, p, q and r are independently selected from 0 to 15 and s is from 1 to 15,

[0208] aa is an amino acid side chain residue;

[0209] A and A' are independently selected from O, S, NH, NR, NHC(O), NRC(O), CH ₂ , CHR, CHNH ₂ , C(O), C(0)0, C(0)NH, OC(O), and CH=CH, wherein R is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted arylalkyl, optionally substituted cycloalkylalkyl and optionally substituted heterocyclylalkyl; and

[0210] B is selected from, hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted cycloalkyl, optionally substituted aryloxy, and optionally substituted heterocyclyloxy; optionally substituted cycloalkyloxy, C0 ₂ H; and

[0211] wherein m, n, o, p, q, r, s, aa, A, A' and B are such that the longest continuous chain of atoms in a group of formula (i)-(iv) is from 1 to 15 atoms long; [0212J or salt, derivative or prodrug thereof.

(0213) Suitably, the compounds of formulae (I) and (IC) have an IC ₅₀ activity for inhibition of PLA2G2A at a concentration of 50 μΜ or less.

[0214] In some embodiments, the compounds of formulae (I) and (IC) have any one or more of the following features:

[0215] Q is a group of formula (a);

]0216] X contains the moiety -CRR'-; and

[0217] R' is hydrogen with R as defined above, i.e., both R and R' can be hydrogen or just R' can be hydrogen.

[0218] Suitably, X is selected from the group consisting of: CH ₂ C0 ₂ H, CHRC0 ₂ H, CH ₂ - tetrazolyl, CHR-tetrazolyl, CH ₂ S0 ₃ H, CHRSOjH, CH ₂ P(0)(OH) ₂ , CH ₂ P(0)(OHXOR"),

CHRP(OXOH) ₂ , CHRP(OXOHXOR"), CH ₂ CH ₂ C0 ₂ H, CHRCH ₂ C0 ₂ H, CH ₂ CH ₂ -tetrazolyl, CHRCH ₂ - tetrazolyl, CHCH ₂ S0 ₃ H, CHRCH ₂ S0 ₃ H, CH ₂ CH ₂ P(0)(OH) ₂ , CH ₂ CH ₂ P(0)(OH) ₂

CHRCH ₂ P(0)(OH)2, CH ₂ CH ₂ P(OXOH)(OR"), CHRCH ₂ P(0)(OH)(OR") and OP(0)(OH)R'.

(0219] In some embodiments, X, R and R' are independently selected from alkyl, arylalkyl, cycloalkylalkyl and heterocyclylalkyl (where alkyl is a CMS alkyl or a CMS alkylene chain as appropriate) each of which may be substituted or unsubstituted. Non-limiting examples include Cn ₅ alkyl, C4.7 cycloalkylalkyl, benzyl, phenylethyl, phenylpropyl, phenylbutyl, phenylpentyl, phenylhexyl, pyridylmethyl, pyridylethyl, hydroxyalkyl, alkoxyalkyl and arylalkyloxyalkyl.

[0220] In some embodiments, Y is a group of formula (i) or (ii). Non-limiting examples of aa include the side chain residues from amino acids such as histidine, tryptophan, serine, tyrosine, ^J cysteine, threonine, glutamic acid, aspartic acid, lysine, arginine, β-alanine, ornithine, phenylalanine, glutamine, and their homo derivatives. In these examples, m is 0 or 1 and n can be independently 0 or 1 or 2 or 3 or 4 or 5. In one preferred form, m + n is at least 5. An exemplary Y group is derived from homotyrosine or tyrosine or tryptophan or histidine.

[0221] m, n, o, p, q, r, s, aa, A, A' and B are such that the longest continuous chain of atoms in a group of formula (i)-(iv) is from 2 to 15 atoms long, 3 to 15 atoms long, 4 to 15 atoms long or 5 to 15 atoms long, especially 3 to 15 atoms long, 4 to 15 atoms long or 5 to 15 atoms long.

[0222] In some embodiments, the compounds of formulae (I) and (IC) have any one or more of the following features:

[0223] B is selected from optionally substituted C4.7 cycloalkyl, optionally substituted phenyl and optionally substituted 5- or 6-membered heterocyclyl; and

[0224] A and A' are independently CH=CH or CH ₂ . [0225] In illustrative examples of this type, Z is an alkyl chain of 6 to 1 1 carbon atoms length or an alkenyl chain, having one or two double bonds, of 6 to 1 1 carbon atoms in length.

[0226] In some embodiments, A or A' is O while the other is CH ₂ or CH=CH.

[0227] In illustrative examples of this type, Z is a C5-C7 alkyl chain or a C5-C7 alkenyl (having one or two double bonds) chain terminated by an optionally substituted phenyl group, 5-6- membered heterocyclyl ring or 5-6-membered cycloalkyl ring.

[0228] In specific embodiments, the com ounds are represented by formula (IA):

[0229]

[0230] wherein X is CRR'C0 ₂ H or CHRCH ₂ C0 ₂ H, Y is a group of any one of formula (i)- (iv) and Z is a group of formula (iii) or (iv), as defined above.

[0231] In some embodiments according to formula (IA), the B moiety of Y is an optionally substituted phenyl group, an optionally substituted C4-C7 cycloalkyl group or an optionally substituted 5-6-membered heterocycle. Suitably, B is an optionally substituted phenyl group or an optionally substituted pyridyl group.

[0232] In other specific embodiments, the compounds are represented by formula (IB):

[0233] wherein:

[0234] X is selected from the group consisting of:

[0235] CRR'C0 ₂ H, CRR'-tetrazoIyl, CRR'S0 ₃ H, CRR* P(0)(OH) ₂ , CRR ¹ P(0)(OH)(OR"), CHRCH ₂ C0 ₂ H, CHRCHrtetrazolyl, CHRCH ₂ S0 ₃ H, CHRCH ₂ P(0)(OH) ₂ , CHRCH ₂ P(0)(OH)(OR"), OP(0)(OH)R', NRSOjH, NRP(0)(OH) ₂ , NRP(0)(OH)(QR")

[0236] wherein R, R' and R" are independently selected from hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted acyl, optionally substituted arylalkyl, optionally substituted cycloalkylalkyl and optionally substituted heterocyclylalkyl, except that R" is not hydrogen;

[0237] Q is a group selected from formulae (a)-(g): <

[02

(a) (b) (c)

(d) (e) (f) (g)

[0239] Rioo is optionally substituted cycloalkyl;

[0240] Z is a group selected from formulae (i)-(iv):

[0241] (i) -(CH ₂ ) _m -aa-(CH ₂ ) _N -B; or

[0242] (ii) -(CH ₂ ) _m -aa-(CH ₂ ) _N -A-(CH ₂ ) ₀ -B; or

[0243] (iii) -(CHJ A-CCHJ AHCHJ -B; or

[0244] (iv) -(CH ₂ ) _S -B;

[0245] wherein

[0246] m is 0 or 1 , n, o, p, q and r are independently selected from 0 to 15 and s is from 5 to 15,

[0247] aa is an amino acid side chain residue;

[0248] A and A' are independently selected from O, S, NH, NR, NHC(O), NRC(O), CH ₂ , CHR, CHNH ₂ , C(O), C(0)0, C(0)NH, OC(O), and CH=CH, wherein R is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted arylalkyl, optionally substituted cycloalkylalkyl and optionally substituted heterocyclylalkyl; (0249] B is selected from, hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted cycloalkyl, optionally substituted aryloxy, and optionally substituted heterocyclyloxy; optionally substituted cycloalkyloxy, C0 ₂ H; and

[0250] wherein m, n, o, p, q, r, s, aa, A, A' and B are such that the longest continuous chain of atoms in a group of formula (i)-(iv) is from 5 to 15 atoms long;

[0251] or salt, derivative or prodrug thereof.

[0252] In particular embodiments, the compounds of formula (IB) are selected from compounds of formula (ID):

[0254] wherein J is selected from -CH ₂ -, -CH=CH-, -O- and -S-;

[0255] R300 is selected from cycloalkyl;

[0256] R 00 is selected from optionally substituted aryl and optionally substituted heterocyclyl; and

[0257] u is an integer from 1 to 5 or a pharmaceutically acceptable salt thereof.

[0258] In some embodiments of formula (IB) or formula (ID), R100 or R ₃₀ o are selected from C3. ₈ cycloalk l, especially G^cycloalkyl, more especially C ₅ . ₆ cycloalkyl-. Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptanyl, and cyclooctanyl, especially cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptanyl, more especially cyclopentyl and cyclohexyl.

[0259] In articular embodiments, the compounds of formula (ID) are selected from:

[0260]

[0261) Compound (i): = -CH ₂ CH ₂ - and v is 2;

[0262] Compound (ii): K is -CH ₂ -0- and v is 2;

[0263] Compound (iii): K is -CH=CH- and v is 2; and

[0264] Compound (iv): K is -CH ₂ CH ₂ - and v is 1 or a pharmaceutically acceptable salt thereof.

[0265] In specific embodiments, the com ounds are represented by formula (I):

[0266]

[0267] wherein:

[0268] X is selected from the group consisting of:

[0269] CRR'C0 ₂ H, CRR'-tetrazolyl, CRR'S0 ₃ H, CRR' P()(OH) ₂ , CRR' P(0)(OH)(OR"), CHRCH ₂ C0 ₂ H, CHRCH ₂ -tetrazolyl, CHRCH ₂ S0 ₃ H, CHRCH ₂ P(0)(OH) ₂ , CHRCH ₂ P(0)(OH)(OR"), OP(0)(OH)R', NRS0 ₃ H, NRP(OXOH) _2> NRP(0)(OHXOR")

[0270] wherein R, R' and R" are independently selected from hydrogen, optionally substituted alkyi, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted acyl, optionally substituted arylalkyi, optionally substituted cycloalkylalkyl and optionally substituted heterocyclylalkyl, except that R" is not hydrogen;

[0271] Q is a roup of formula (a)

[02721 (a)

[0273] Y is a group of formula

[0274] (i) -(CH ₂ ) _m -aa-(CH ₂ ) _n -B;

[0275] and Z is a group of formula

[0276] (iii) -(CH^ _p -A-tCHz A'-CCHz -B

[0277] wherein [0278] m is 0 or 1, n, o, p, q and r are independently selected from 0 to 15;

[0279] aa is an amino acid side chain residue provided that the amino acid is not cysteine or homocysteine;

[0280] A and A' are independently selected from O, S, NH, NR, NHC(O), NRC(O), CH ₂ , CHR, CHNH ₂ , C(O), C(0)0, C(0)NH, OC(O), and CH=CH, wherein R is selected from optionally substituted alkyl, optionall substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted arylalkyl, optionally substituted cycloalkylalkyl and optionally substituted heterocyclylalkyl; and

[0281] B is selected from, hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted cycloalkyl, optionally substituted aryloxy, and optionally substituted heterocyclyloxy; optionally substituted cycloalkyloxy, 0Ο ₂ Η; and

[0282] wherein m, n, 0, p, q, r, s, aa, A, A' and B are such that the longest continuous chain of atoms in a group of formula (i) or (iii) is from 5 to 15 atoms long; and

[0283] provided that the optional substituents are not mercapto, alkylthio, benzylthio or acylthio;

[0284] wherein the compound of formula (I) has an IC50 activity for PLA2G2A at a concentration of 50 uM or less, _{. .} ^r

[0285] or salt or prodrug thereof.

[0286] In certain of these embodiments, X is selected from the group consisting of:

CH ₂ C0 ₂ H, CHRCO2H, CH ₂ -tetrazolyl, CHR-tetrazolyl, CH ₂ S0 ₃ H, CHRSO ₃ H, CH ₂ P(0)(OH) ₂ , CH ₂ P(0)(OH)(OR"), CHRP(0)(OH) ₂ , CHRP(0)(OH)(OR"), CH2CH2CO2H, CHRCH ₂ C0 ₂ H, CH ₂ CH ₂ -tetrazolyI, CHRCH ₂ -tetrazolyl, CHCH2SO ₃ H, CHRCH ₂ S0 ₃ H, CH ₂ CH ₂ P(0)(OH) ₂ , CH ₂ CH ₂ P(0)(OH>2 CHRCH ₂ P(0)(OH) ₂ , CH ₂ CH ₂ P(0)(OH)(OR"), CHRCH ₂ P(OXOH)(OR") and OP(0)(OH)R'. In illustrative examples of this type, R, R' and R" are independently selected from hydrogen, alkyl, arylalkyl, cycloalkylalkyl and heterocyclylalkyl, wherein each alkyl, arylalkyl, cycloalkylalkyl and heterocyclylalkyl may be substituted or unsubstituted except that R" is not hydrogen. For example R, R' and R" may be independently selected from hydrogen, C].i ₅ alkyl, C4.7 cycloalkylalkyl benzyl, phenylethyl, phenylpropyl, phenylbutyl, phenylpentyl, phenylhexyl, pyridylmethyl, pyridylethyl, pyridyipropyl, pyridylbutyl, pyridylpentyl and pyridylhexyl wherein each of Ci-15 alkyl, C ₄ . ₇ cycloalkylalkyl, benzyl, phenylethyl, phenylpropyl, phenylbutyl, phenylpentyl, phenylhexyl, pyridylmethyl, pyridylethyl, pyridyipropyl, pyridylbutyl, pyridylpentyl and pyridylhexyl may be substituted or unsubstituted except that R" is not hydrogen. In specific examples, at least one of R and R' is hydrogen. [0287] In certain of these embodiments, X is selected from the group consisting of CRR'C0 ₂ H, CRR'-tetrazolyl, CRR'S0 ₃ H, CRR'P(0)(OH) ₂ and CRR'P(0)(OH)(OR").

[0288] In certain of these embodiments, the aa is a side chain residue from the group of amino acids consisting of histidine, tryptophan, serine, tyrosine, cysteine, threonine, glutamic acid, aspartic acid, lysine, arginine, β-alanine, ornithine, phenylalanine, glutamine, and their homo derivatives. In these examples, m is 0 or 1 and n can be independently 0 or 1 or 2 or 3 or 4 or 5. In one preferred form, m + n is at least 5.

[0289] In certain of these embodiments, B is selected from optionally substituted C4.7 cycloalkyl, optionally substituted phenyl and optionally substituted 5- or 6-membered heterocyclyl.

[0290] In certain of these embodiments, A and A' are independently CH=CH or CH ₂ .

(0291] In certain of these embodiments, Z is an alkylchain of 6 to 1 1 carbon atoms in length or an alkenyl chain, having one or two double bonds, of 6 to 1 1 carbon atoms in length.

[0292] In certain of these embodiments, A or A' is O while the other is C¾ or CH=CH.

[0293] In certain of these embodiments, Z is a C ₅ -C7 alkyl chain or a C5-C7 alkenyl (having one or two double bonds) chain terminated by an optionally substituted phenyl group, 5-6- membered heterocyclyl ring or 5-6-membered cycloalkyl ring.

[0294] Non-limiting examples of compounds according to formula I and formula LA are selected from:

(86) R ^A = R ^B = H, t = 5, D = CH

(87) R ^A = R ^B = H, t = 7, D = CH

(85) R ^A = R ^B = H, t = 6, D = CH

(88) R ^A = H, R ^B = OMe, t = 6, D = CH

(89) R ^A = NHCOMe, R ^B = H, t = 6, D = CH

(90) R ^A = H, R ^B = N0 ₂₎ t = 6, D = CH

[0295] (91) R ^A = R ^B = H, t = 6, D = N

(95) E = N, F = CH

[0296] (96) E = CH,F=N [0297] In specific embodiments, the compounds are selected from:

[0300] Inhibitor compounds according to formulae (I) and (IA) for use in the present invention may be generated using the synthesis methods disclosed in U.S. Pat. No. 7,253, 194 (Reid), or using any other synthesis method known in the art.

[0301] In other embodiments, the PLA2G2A small molecule inhibitor is selected from carbazole derivative compounds. Representative compounds of this type are described for example in U.S. Pat. No. 6,933,313 (Harper), which is expressly incorporated herein by reference in its entirety.

[0302] Non-limiting PLA2G2A inhibitors of this type have a structure represented by formula (II):

[0304] wherein:

[0305] Z is cyclohexenyl, or phenyl;

[0306] selected from groups (a), (b) and (c) where: [0307] (a) is— (CrC ₂₀ )alkyl,— (C ₂ -C ₂₀ )alkenyl,— (C ₂ -C ₂ o)alkynyl, carbocyclic radicals, or heterocyclic radicals, or

[0308] (b) is a member of (a) substituted with one or more substituents selected from hydrogen,— <C,-C ₆ )alkyl,— <C ₂ -C ₆ )alkenyl,— (C ₂ -C ₆ )alkynyl,— (C ₃ -C ₈ )cycloalkyl,"— <C,- C8)alkoxy, halogen or phenyl (Ci-C ₄ )alkyl;

[0309) (c) is the group— (L)— R ⁸⁰ ; where,— (L)— is a divalent linking group of 1 to 12 atoms selected from carbon, hydrogen;

[0310] R ² ' is hydrogen,— <C _r C ₆ )aIkyl,— (C ₂ -C ₆ )alkenyl,— (C C ₆ )alkynyl,— (C ₃ - C ₈ )cycloalkyl,"— (C _r C6)alkoxy, halogen or phenyl (CpG alkyl, where f is 1-3;

[0311] R ¹ is— NHNR ³⁰ R ³¹ ,— NR ³⁰ R ³ ' , or— CONR ³⁰ R ³¹ , where R ³⁰ and R ³¹ are each independently hydrogen or— -(Ci-C6)alkyl;

[0312] R ² is— CONR V, where R ⁴⁰ — OH,— 0(C,-C ₈ )alkyl,— 0(C C ₈ )alkenyl,— 0(C ₃ -C ₈ )cycloalkyl,— O(aryl) and— 0(C _r C ₈ )alkylaryl; and R ⁴¹ is hydrogen,— (C _r C ₈ )alkyl,— <C ₂ - C ₈ )alkenyl,— (C ₃ -C ₈ )cycloalkyl, aryl and— (Ci-C ₈ )alkylaryl; where j is 1 to 3 both inclusive; and

[0313] R ³ is selected from hydrogen,— <C _r C ₆ )alkyl,— <C ₂ -C ₆ )alkenyl,— (C ₂ -C ₆ )alkynyl, — (CrCg)cycloalkyl,"— (Ci-C ₆ )alkoxy, halogen, phenyl (Ci-C^alkyl, optionally substituted carbocyclic and optionally substituted heterocyclic, wherein the substituent is selected from hydrogen, <—{CrC ₆ )&\ky\,— <C ₂ -C ₆ )alkenyl,— <C ₂ -C ₆ )alkynyl,— C ₃ -C ₈ )cycloalkyl,"— (C C ₆ )alkoxy, halogen and phenyl (Ci-C ₄ )alkyl, or a pharmaceutically acceptable solvate or salt, thereof.

[0314] In specific embodiments, the ^" carbazole derivative PLA2G2A inhibitors are represented by formula (III):

[0316] wherein:

[0317] Z is cyclohexenyl, or phenyl;

[0318] R ¹ is— NHNR ³⁰ R ³¹ ,— NR ³⁰ R ³¹ , or—CONR ³⁰ R ³¹ , where R ³⁰ and R ³¹ are each independently hydrogen or— (C _r C ₆ )alkyl; (0319] R ² is— CONR ⁴⁰ R ⁴¹ , where R ⁴⁰ is— OH,— 0(C _r C ₈ )alkyl,— 0(C ₂ -C ₈ )alkenyl,— 0(C ₃ -C ₈ )cycloalkyI,— O(aryl) or— 0(C _r C ₈ )alkylaryl; and R ⁴¹ is hydrogen,— <C,-C ₈ )alkyl,— <C ₂ - C ₈ )aikenyl,— (C ₃ -C ₈ )cycIoaIkyl, aryl or— (Ci-C ₈ )a!kylaryl; where j is 1 to 3 both inclusive;

[0320] R ³ is hydrogen,— 0(C,-C ₆ )alkyl, halo,— (CrC ₆ )alkyl,— <C ₂ -C ₆ )alkenyl,— {C ₂ - C ₆ )alkynyl,— (C ₃ -C ₈ )cycloalkyl, phenyl,— (C]-C ₄ )alkylphenyl; phenyl substituted with— (d-

C ₆ )alkyl, halo, or—CF ₃ ;— CH ₂ 0Si(C _r C ₆ ) ₃ atkyl, furyl, thiophenyl,— (C,-C ₆ )hydroxyalkyl,— (C,- C ₆ )alkoxy(C,-C ₆ )alkyl,— (C,-C ₆ )atkoxy(Ci-C6)alkenyl, and— <CH ₂ ) _n R ⁸ , where R ⁸ is hydrogen,— CONH ₂ ,— NR ⁹ R ¹⁰ ,— CN or phenyl, where R ⁹ and R ¹⁰ are independently hydrogen,— CF ₃ , phenyl, — (C|-C ₄ )alkyl,— (C]-C ₄ )alkylphenyl or-phenyI(Ci-C ₄ )alkyl and n is 1 to 8; and

[0321] R ⁴ is hydrogen,— (Ci-Ci ₄ )alkyl,— {C ₃ -C _]4 )cycloalkyl, pyridyl, phenyl or phenyl substituted with from 1-5 substituents selected from the group consisting of— (Ci-CeJalkyl, halo,— CF ₃ ,— OCF ₃ ,— (C,-C )alkoxy,— CN,— (C,-C ₄ )alkylthio,— <C _r C )alkylphenyl, phenyl, phenoxy and— OR ⁹ ; where R ⁹ is independently hydrogen,— CF ₃ , phenyl,— (C|-C ₄ )alkyl,— (Ci- C ₄ )alkylphenyl; tetrazole or tetrazole substituted with— (C _r C ₄ )aIkyl or— (C _r C )alkylphenyl; or naphthyl; and

[0322] R ²¹ is hydrogen, halo,— (C _r C ₃ )alkyl,— (C ₃ -C ₄ )cycloalkyl,— (C ₃ -C ₈ )cycloalkenyl, — 0(C)-C ₂ )alkyl and— S(C _r C ₂ )alkyl where f is 1 to 3 or a pharmaceutically acceptable solvate or salt, thereof.

[0323] In illustrative examples, the compounds of formula (III) have the following features:

[0324J R' is— NH ₂ ;

[03251 R ² is— CONR ⁴⁰ R ⁴ ' where R ⁴⁰ is—OH,— 0(C,-C ₈ )alkyl,— 0(C ₂ -C ₈ )alkenyl,— 0(C ₃ -C ₈ )cycloalkyl,— O(aryl) or— (C _r C ₈ )alkylaryl; and R ⁴¹ hydrogen,— (Ci-C ₈ )alkyl,— <C ₂ - C ₈ )alkenyl,— (C ₃ -C ₈ )cycloalkyl, aryl or— (C|-C ₈ )alkylaryl; where j is 1 ;

[0326] R ³ is hydrogen,— {C-Ceialkyl,— (C ₂ -C ₆ )alkenyl,— (C ₂ -C ₆ )alkynyl,— (C ₃ -

C ₈ )cycloalkyl,— (C)-C ₆ )alkoxy, halo or-phenyl (C C ₄ )alkyl;

[0327] R ⁴ is phenyl or phenyl substituted with from 1-5 substituents selected from the group consisting of— (C,-C ₆ )alkyl, halo,— CF ₃ ,— OCF ₃ ,— (Ci-C ₄ )alkoxy,— CN,— (C _r

C ₄ )alkylthio, phenyl (Ci-C ₄ )alkyl,— (C|-C ₄ )alkylphenyl, phenyl, phenoxy or— OR ⁹ ; where R ⁹ is independently hydrogen,— CF ₃ , phenyl,— (C _r C )alkyl,— (C _r C ₄ )alkylphenyl or-phenyl(C _r C )alkyl; tetrazole; tetrazole substituted with— (Ci-C ₄ )alkyl or— (C C ₄ )alkylphenyl;

[0328] R ²¹ is hydrogen, halo,— (C,-C ₃ )alkyl,— (C ₃ -C ₄ )cycloalkyI,— <C ₃ -C ₄ )cycloalkertyl, — 0(Ci-C ₂ )alkyl and— S(C,-C ₂ )alkyl where f is 1 ; and

[0329] Z is phenyl or a pharmaceutically acceptable solvate or salt thereof. [0330] In certain non-limiting examples, the compounds of formula (HI) have the following features:

[0331] R ²¹ is hydrogen; R ³ is hydrogen; and R ⁴ is phenyl or phenyl substituted with from 1-5 substituents selected from the group consisting of— (Ci-CeJalkyl, halo,— CF ₃ ,— OCF3 ,— (C|- Gi)alkoxy,— CN,— (Ci-Gi)alkylthio, phenyl (Ci-C ₄ )alkyl,— (Ci-C ₄ )alkylphenyl, phenyl, phenoxy or — OR ; where R ⁹ is independently hydrogen,— CF ₃ , phenyl,— (Ci-G alkyl,— (Ci-C4)alkylphenyl or-phenyl (Ci-C ₄ )alkyl; or a pharmaceutically acceptable solvate or salt thereof.

[0332] In certain embodiments, carbazole derivative compounds represented by formula (II) or formula (III) are selected from: [[5-Carbamoyl-9-(phenylmethyl)carbazol-4-yl]oxy]-N- (hydroxy)acetamide; [[5-Carbamoyl-9-(phenylmethyl)carbazol-4-yl]oxy]-N-(methoxy) acetamide [[5- Carbamoyl-9-(phenylmethyI)carbazoI-4-yl]oxy]-N-(ethoxy)aceta mide; [[5-Carbamoyl-9- (phenylmethyl)carbazol-4-yl]oxy]-N-[(phenylmethyl)oxy]acetam ide; [[5-Carbamoyl-9- (phenylmethyl)carbazol-4-yl]oxy]-N-(methoxy)-N-(methyl)aceta mide; [[5-Carbamoyl-9- (phenylmethyl)carbazol-4-yl]oxy]-N-(phenyloxy)acetamide; [[5-Carbamoyl-9-(phenylmethyl)-2- (thien-2-yl)carbazol-4-yl]oxy]-N-[(phenylmethyl) oxy]acetamide; or a pharmaceutically acceptable solvate or salt thereof.

[0333] Alternatively, the carbazole derivative compounds are selected from those described in EP 952149, which is expressly incorporated herein by reference in its entirety. In some embodiments, these compounds are selected from: 9-benzyl-5,7-dimethoxy-l,2,3,4- tetrahydrocarbazole-4-carboxylic acid hydrazide; 9-benzyl-5,7-dimethoxy-l ,2,3,4- tetrahydrocarbazole-4-carboxamide; [9-benzyl-4-carbamoyl-7-methoxy-l,2,3,4-tetrahydrocarbazol-5 - yl]oxyacetic acid; [9-benzyl-4-carbamoyl-7-methoxycarbazol-5-yl]oxyacetic acid; methyl [9-benzyl-4- carbamoyl-7-methoxycarbazolr5-yl]oxyacetic acid; 9-benzyl-7-methoxy-5-cyanomethyloxy- 1 ,2,3,4- tetrahydrocarbazole-4-carboxamide; 9-benzyI-7-methoxy-5-(lH-tetrazol-5-yl-methyl)oxy)-l,2,3,4- tetrahydrocarbazole-4-carboxamide; {9-[(phenyl)methyl]-5-carbamoyl-2-methyl-carbazol-4- yljoxyacetic acid; {9-[(3-fluorophenyl)methyl]-5-carbamoyI-2-methylcarbazoI-4-y l}oxyacetic acid; {9-[(3-methylphenyI)methyl]-5-carbamoyl-2-methylcarbazol-4-y l}oxyacetic acid; {9- [(phenyl)methyl]-5-carbamoyl-2-(4-trifluoromethylphenyl)-car bazol-4-yl} oxyacetic acid; 9-benzyI-5- (2-methanesulfonamido)ethyloxy-7-methoxy-l,2,3,4-tetrahydroc arbazole-4-carboxamide; 9-benzyl-4- (2-methanesuIfonamido)ethyloxy-2-methoxycarbazole-5-carboxam ide; 9-benzyl-4-(2- trifluoromethanesulfonamido)ethy!oxy-2-methoxycarbazole-5-ca rboxamide; 9-benzyl-5- methanesulfonamidoylmethyloxy-7-methoxy- 1 ,2,3,4-tetrahydrocarbazole-4-carboxamide; 9-benzyl-4- methanesulfonamidoylmethyloxy-carbazole-5-carboxamide; [5-carbamoyl-2-pentyl-9- (phenyImethyl)carbazol-4-yl]oxyacetic acid; [5-carbamoyl-2-(l-methylethyl)-9- (phenylmethyl)carbazol-4-yl]oxyacetic acid; [5-carbamoyl-9-(phenylmethyl)-2-[(tri(-l- methylethyl)silyl)oxymethyl]carbazol-4-yl]oxyacetic acid; [5-carbamoyl-2-phenyl-9- (phenylmethyl)carbazol-4-yl]oxyacetic acid; [5-carbamoyl-2-(4-chlorophenyl)-9- (phenylmethyl)carbazol-4-yl]oxyacetic acid; [5-carbamoyl-2-(2-furyl)-9-(phenylmethyl)carbazol-4- yl]oxyacetic acid; [5-carbamoyl-9-(phenyImethyl)-2-[(tri(- 1 -methylethyI)silyl)oxymethyl]carbazol-4- yl]oxyacetic acid; {9-[(2-Fluorophenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacet ic acid; {9-[(2- trifIuoromethylphenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyac etic acid; {9-[(2- benzylphenyl)methyl]-5-carbamoylcarbazol-4-yl} oxyacetic acid; {9-[(l -naphthyl)methyI]-5- carbamoyIcarbazol-4-yl}oxyacetic acid; {9-[(2-cyanophenyl)methyl]-5-carbamoylcarbazol-4- yljoxyacetic acid; {9-[(3-cyanophenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyaceti c acid; {9-[(3,5- dimethylphenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid; {9-[(3-iodophenyl)methyl]-5- carbamoylcarbazol-4-yl}oxyacetic acid; {9-[(2-Chlorophenyl)methyI]-5-carbamoyIcarbazol-4- yl}oxyacetic acid; {9-[(2,3-difluorophenyl)methyl]-5-carbamoylcarbazol-4-yl}oxy acetic acid; {9- [(2,6-difluorophenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyace tic acid; {9-[(2,6- dichlorophenyl)methyl]-5-carbamoylcarbazoI-4-yl}oxyacetic acid; {9-[(2-biphenyl)methyl]-5- carbamoylcarbazol-4-yl } oxyacetic acid; {9-[(2-Biphenyl)methyl]-5-carbamoylcarbazol-4- yl}oxyacetic acid methyl ester; [9-Benzyl-4-carbamoyl-l ,2,3,4-tetrahydrocarbazole-5-yl]oxyacetic acid; {9-[(2-Pyridyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid; {9-[(3-Pyridyl)methyl]-5- carbamoylcarbazol-4-yI} oxyacetic acid; [9-benzyl-4-carbamoyl-8-methyl-l,2,3,4-tetrahydrocarbazol- 5-yl]oxyacetic acid; [9-benzyl-5-carbamoyl-l-methylcarbazol-4-yl]oxyacetic acid; [9-benzyl-4- carbamoyl-8-fluoro-l,2,3,4-tetrahydrocarbazol-5-yl]oxyacetic acid; [9-benzyl-4-carbamoyl-8-chloro- l ,2,3,4-tetrahydrocarbazol-5-yl]oxyacetic acid; [5-carbam0yl-9-(phenylmethyl)-2-[[(propen-3- yl)oxy]methyl]carbazoI-4-yl]oxyacetic acid; [5-carbamoyl-9-(phenylmethyl)-2- [(propyloxy)methyl]carbazol-4-yl]oxyacetic acid; 9-benzyl-7-methoxy-5-((carboxamidomethyl)oxy)- 1 ,2,3,4-tetrahydrocarbazole-4-carboxamide; 9-benzyl-7-methoxy-5-cyanomethyloxy-carbazole-4- carboxamide; 9-benzyl-7-methoxy-5-((lH-tetrazol-5-yl-methyl)oxy)-carbazol e-4-carboxamide; 9- benzyl-7-methoxy-5-((carboxamidomethyl)0xy)-carbazole-4-carb oxamide; and [9-Benzyl-4- carbamoyl-l,2,3,4-tetrahydrocarbazole-5-yl]oxyacetic acid or a pharmaceutically acceptable racemate, solvate, tautomer, optical isomer, prodrug derivative selected from the methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, morpholinoethyloxy, diethylglycolamide or

diethylaminocarbonyl methoxy ester or salt, thereof.

[0334] In still other embodiments, a PLA2G2A small molecule inhibitor for use in the compositions and methods disclosed herein may be an indole-based PLA2G2A inhibitor, meaning that the compound contains an indole nucleus having the structure:

[0335J [0336] A variet of indole-based PLA2G2A inhibitors are known in the art. For example, indole-based PLA2G2A inhibitors that may be used in conjunction with the present invention include but are not limited to those set forth in U.S. Pat. Nos. 5,654,326 (Bach); 5,733,923 (Bach); 5,919,810 (Bach); 5,919,943 (Bach); 6,175,021 (Bach); 6,177,440 (Bach); 6,274,578 (Denney); and 6,433,001 (Bach), the entire disclosures of which are incorporated by reference herein. Methods of making indole-based PLA2G2A inhibitors are set forth in, for example, U.S. Pat. Nos. 5,986,106 (Khau); 6,265,591 (Anderson); and 6,380,397 (Anderson), the entire disclosures of which are incorporated by reference herein. PLA2G2A inhibitors for use in the present invention may be generated using these synthesis methods, or using any other synthesis method known in the art. Various examples of indole- based PLA2G2A inhibitors are set forth below.

[0337] In certain embodiments, PLA2G2A small molecule inhibitors for use in the current invention are lH-indole-3-glyoxylamide compounds having the structure:

[0339] , wherein: each X is independently oxygen or sulfur; R| is selected from the group consisting of (a), (b), and (c), wherein:

[0340] (a) IS C7-C20 alkyl, C7-C20 alkenyl, C ₇ -C ₂ o alkynyl, carbocyclic radicals, Or heterocyclic radicals;

[0341] (b) is a member of (a) substituted with one or more independently selected non- interferirig substituents; and

[0342] (c) is the group— (L)— R ₈ o, where,— (L)— is a divalent linking group of 1 to 12 atoms selected from carbon, hydrogen, oxygen, nitrogen, and sulfur, wherein the combination of atoms in— (L)— are selected from the group consisting of (i) carbon and hydrogen only, (ii) sulfur only, (Hi) oxygen only, (iv) nitrogen and hydrogen only, (v) carbon, hydrogen, and sulfur only, and (vi) carbon, hydrogen, and. oxygen only; and where Rgo is a group selected from (a) or (b);

[0343] R ₂ is hydrogen, halo, C1-C3 alkyl, C3-C4 cycloalkyl, C3-C4 cycloalkenyl,

— O— (C|-C ₂ alkyl),— S— (C _t -C ₂ alkyl), or a non-interfering substituent having a total of 1 to 3 atoms other than hydrogen; [0344] R4 and R ₅ are independently selected from the group consisting of hydrogen, a non- interfering substituent, and— (L ₈ )— (acidic group), wherein— (L _a )— is an acid linker having an acid linker length of 1 to 4; provided that at least one of R and

[0345J R ₅ must be— (L _a )— (acidic group);

[0346] Ri and R ₇ are each independently selected from hydrogen, non-interfering substituents, carbocyclic radicals, carbocyclic radicals substituted with non-interfering substituents, heterocyclic radicals, and heterocyclic radicals substituted with non-interfering substituents; provided that for any of the groups R|, Re, and R7, the carbocyclic radical is selected from the group consisting of cycloalkyl, cycloalkenyl, phenyl, naphthyl, norbornanyl, bicycloheptadienyl, toluoyl, xylenyl, indenyl, stilbenzyl, terphenylyl, diphenylethylenyl, phenyl-cyclohexenly, acenaphthylenyl, and anthracenyl, biphenyl, bibenzylyl and related bibenzylyl homologues represented by the formula (bb),

[0348] where n is a number from 1 to 8; provided, that for any of the groups R _\ , Re, and R ₇ , the heterocyclic radical is selected from the group consisting of pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, pheny!imidazolyl, triazolyl, isoxazolyl, oxazolyl, thiazolyl, thiadiazolyl, indolyl, carbazolyl, norharmanyl, azaindolyl, benzofuranyl, dibenzofuranyl, thianaphtheneyl, dibenzothiophenyl, indazolyl, imidazo(1.2-A)pyridinyl, benzotriazolyl, anthranilyl, 1 ,2- benzisoxazolyl, benzoxazolyl, benzotriazolyl, purinyl, pryidinyl, dipyridylyl, phenylpyridinyl, benzylpyridinyl, pyrimidinyl, phenylpyrimidinyl, pyrazinyl, 1 ,3,5-triazinyl, quinolinyl, phthalazinyl, quinazolinyl, and quinoxalinyl; and provided that for the groups R _{) (} R2, R4, Rj, R*, and R ₇ the non- interfering substituent is selected from the group consisting of C|-C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C _t alkynyl, C7-C12 aralkyl, C7-C1 ₂ alkaryl, C3-Cg cycloalkyl, C ₃ -Cs cycloalkenyl, phenyl, toluoyl, xylenyl, biphenyl, C _r C ₆ alkoxy, C ₂ -C ₆ alkenyloxy, C ₂ -C ₆ alkynyloxy, C ₂ -Ci ₂ alkoxyalkyl, C ₂ -Ci ₂

alkoxyalkyloxy, C ₂ -C| ₂ alkylcarbonyl, C ₂ -C| ₂ alkylcarbonylamino, C ₂ -C ₎₂ alkoxyamino, C ₂ -C) ₂ alkoxyaminocarbonyl, C ₂ -Ci ₂ alkylamino, C]-C ₆ alkylthio, C ₂ -C| ₂ alkylthiocarbonyl, Ci-C ₆

alkylsulfinyl, C|-C ₆ alkylsulfonyl, C ₂ -C ₆ haloalkoxy, Ci-C ₆ haloalkylsulfonyl, C ₂ -Ce haloalkyl, Ci-C ₆ hydroxyalkyi,— C(0)0(d-C ₆ alkyl),— (CH ₂ )„— O— (C,-C ₆ alkyl), benzyloxy, phenoxy, phenylthio, — (CONHS0 ₂ R),— CHO, amino, amidino, bromo, carbamyl, carboxyl, carbalkoxy,— (CH ₂ )„— C0 ₂ H, chloro, cyano, cyanoguanidinyl, fluoro, guanidino, hydrazide, hydrazino, hydrazido, hydroxy, hydroxyamino, iodo, nitro, phosphono,— SO ₃ H, thioacetal, thiocarbonyl, and CpCe carbonyl, where n is from 1 to 8; and pharmaceutically acceptable salts, solvates, prodrug derivatives, racemates, tautomers, or optical isomers thereof.

[0349] In certain of these embodiments,— (L)— has the formula:

[0351] wherein Rgi and R _¾2 are each independently selected from the group consisting of hydrogen, Ci-Cio alkyl, carboxy, carbalkoxy, and halo; p is a number from 1 to 5; and Z is selected from the group consisting of a bond,— (C¾)— ,— O— ,— N(C|-Cio alkyl)-,— NH— , and— S— .

[0352] In certain of these embodiments wherein R4 is— (L _a )— (acidic group), the acid linker— (L _a )— has the formula:

[0354] wherein Q is selected from the group consisting of— (CH ₂ )— ,— O— ,— NH— , and— S— ; and R 3 and Rg ₄ are each independently selected from the group consisting of hydrogen, C I -C IO alkyl, aryl, C 1 -C10 alkaryl, CpCio aralkyl, hydroxy, and halo. ,

[0355] In certain of these embodiments wherein R ₅ is— (L _a )— (acidic group), the acid linker— (L _a )— has the formula:

[0357] wherein r is a number from 2 to 7; s is 0 or 1 ; Q is selected from the group consisting of— (CH_)— ,— O— ,— NH— , and— S— ; and Rg ₅ and Ree are each independently selected from the group consisting of hydrogen, C1 -C10 alkyl, aryl, CrQo alkaryl, C)-Cio aralkyl, carboxy, carbalkoxy, and halo.

¹ [0358] In certain embodiments, a lH-indole-3-glyoxylamide compound for use in the present invention is selected from the group consisting of: ((3-(2-Amino-l,2-dioxoethyl)-2-ethyl-l- (phenylmethyl)-lH-indol-4-yl)oxy)acetic acid; [[3-(2-Amino-l ,2-dioxoethyl)-2-ethyl-l -

(phenylmethyl)-lH-indol-4-yl]oxy]acetic acid methyl ester; ((3-(2-Amino-l ,2-dioxoethyl)-2-methyl- l-(phenylmethyl)-lH-indol-4-yl)oxy)-acetic acid; dl-2-((3-(2- Amino- 1 , 2-dioxoethyl)-2 -methyl- 1 - (phenylmethyl)-lH-indol-4-yl-) oxy)propanoic acid; ((3-(2-Amino-l,2-dioxoethyl)-l-((l , -biphenyl)- 2- !methy l)-2-methyl- 1 H-indol-4-y l)oxy)acetic acid; ((3-(2-Amino- 1 ,2-dioxoethy 1)- 1 -(( 1 , 1 '-bipheny 1)-

3- ylmethyl)-2-methyl-lH-i- ndoI-4-yl)oxy)acetic acid; ((3-(2-Amino-l,2-dioxoethyl)-l-((l, - biphenyl)-4-ylmethyl)-2-methyl-lH-i- ndol-4-yl)oxy)acetic acid; ((3-{2-Amino-l,2-dioxoethyl)-l- ((2,6-dichlorophenyI)methyl)-2-methyl-lH-i- ndol-4-yl)oxy)acetic acid; ((3-(2 -Amino- 1,2- dioxoethyl)- 1 -(4(-fluorophenyl)methyl)-2-methyl- 1 H-indol-4-yl)oxy)acetic acid; ((3-(2-Amino- 1 ,2- dioxoethy l)-2-methyl-l-((l-naphthalenyl)methyl)-lH-indol-4-yl)oxy)ace tic acid; ((3-(2-Amino- l,2- dioxoethyl)-l-((3-chlorophenyl)methyl)-2-ethyl-lH-indol— 4-yl)oxy)acetic acid; ((3-(2-Amino-l ,2- dioxoethyl)-l-((l, -biphenyl)-2-ylmethyI)-2-ethyl-lH-in- dol-4-yl)oxy)acetic acid; ((3-(2-amino-l ,2- dioxoethy!)- 1 -(( 1 , 1 '-biphenyl)-2-ylmethyI)-2-propyl- 1 H-i- ndol-4-yl)oxy)acetic acid; ((3-(2-Amino- l,2-dioxoethyl)-2-cyclopropyl-l-(phenylmethyl)-lH-indol-4-yl -)oxy)acetic acid; ((3-(2-Amino-l ,2- dioxoethyl)- 1 -(( 1 , 1 '-biphenyl)-2-ylmethy l)-2-cyclopropy 1- 1 H-indol-4-yl)oxy)acetic acid; and 4-((3-(2- Amino-l,2-dioxoethyl)-2-ethyl-l-(phenylmethyl)-lH-indol-5-yl )oxy-) butanoic acid, or

pharmaceutically acceptable salts, solvates, prodrug derivatives, racemates, tautomers, or optical isomers thereof.

[0359] In certain embodiments, PLA2G2A inhibitors for use in the current invention lH-indole-3-glyoxylamide compounds having the structure:

[0361] wherein: both X are oxygen;

[0362] Ri is selected from the group consisting of:

[0365] wherein Rio is a radical independently selected from halo, Ci-Cio alkoxy,— S— (Ci-Cio alkyl), and CI-CIO haloalkyl, and t is a number from 0 to 5; R2 is selected from the group consisting of halo, cyclopropyl, methyl, ethyl, and propyl; R4 and R5 are independently selected from the group consisting of hydrogen, a non-interfering substituent, and— (L _a )— (acidic group), wherein — (L _a )— is an acid linker; provided that the acid linker— (L _a )— for R4 is selected from the group consisting of:

[0366] °- ^c ¾i- _and

[0367] provided that the acid linker— (L _a ^■ for R ₅ is selected from the group consisting of:

[0369] wherein R^ and Rgs are each independently selected from the group consisting of hydrogen, Ci-Cio alkyl, aryl, CpCio alkaryl, C1-C1 ₀ aralkyl, carboxy, carbalkoxy, and halo; provided that at least one of R4 and R ₅ must be— (L _a )— {acidic group), and (acidic group) on— (L _a )— (acidic group) of R4 or R ₃ is selected from— C0 ₂ H,— S0 ₃ H, or— P(0)(OH)2 ; R<s and R ₇ are each independently selected from the group consisting of hydrogen and non-interfering substituents, with the non-interfering substituents being selected from the group consisting of: Ci-Ce alkyl, C2-C ₆ alkenyl, C2-C ₆ alkynyl, C ₇ -Ci_ aralkyl, C7-C12 alkaryl, C ₃ -C ₈ cycloalkyl, C ₃ -C ₈ cycloalkenyl, phenyl, toluoyl, xylenyl, biphenyl, Ci-C ₆ alkoxy, C ₂ -C ₆ alkenyloxy, C ₂ -C ₆ alkynyloxy, C2-C12 alkoxyalkyl, C ₂ - Ci2 alkoxyalkyloxy, C2-C12 alkylcarbonyl, C ₂ -Cn alkylcarbonylamino, C ₂ -Ci ₂ alkoxyamino, C ₂ -C ₁ 2 alkoxyaminocarbonyl, C ₂ -Ci ₂ alkylamino, C _r C ₆ alkylthio, C2-C12 alkylthiocarbonyl, C _r C ₆ alkylsulfmyl, CrC ₆ alkylsulfonyl, C ₂ -C ₆ haloalkoxy, Ci-C ₆ haloalkylsulfonyl, C ₂ -C ₆ haloalkyl, C|-C ₆ hydroxyalkyl,— C(0)0(C C ₆ alkyl),— (CH ₂ )„— O— <C _r C ₆ alkyl), benzyloxy, phenoxy, phenylthio, — (CONHSO2 R),— CHO, amino, amidino, bromo, carbamyl, carboxyl, carbalkoxy,— (CH ₂ )„— CO2 H, chloro, cyano, cyanoguanidinyl, fluoro, guanidino, hydrazide, hydrazino, hydrazido, hydroxy, hydroxyamino, iodo, nitro, phosphono,— S0 ₃ H, thioacetal, thiocarbonyl, and C _r C ₆ carbonyl;

wherein n is from 1 to 8; and pharmaceutically acceptable salts, solvates, prodrug derivatives, racemates, tautomers, or optical isomers thereof. [0370] In certain embodiments, l H-indole-3-glyoxylamide compounds for use in the present invention are selected from the group consisting of: ((3-(2-Amino-l,2-dioxoethyl)-2-methyl-l- (phenylmethyl)-lH-indol-4-yl)oxy)- acetic acid; ((3-(2 -Amino- 1 , 2-dioxoethyl)-2-methyl- 1 - (phenylmethyl)- lH-indol-4-yl)oxy)- acetic acid methyl ester; dl-2-((3-(2-Amino-l ,2-dioxoethyl)-2- methyl- 1 -(phenylmethyl)- 1 H-indol-4-yl-)oxy)propanoic acid; dl-2-((3-(2-Amino- 1 ,2-dioxoethy l)-2- methyl-l-(phenylmethyl)-lH-indol-4-yl-)oxy)propanoic acid methyl ester; ((3-(2-Amino-l,2- dioxoethyl)-l-((l,l'-biphenyl)-2-ylmethyl)-2-methyl-lH-i- ndol-4-yl)oxy)acetic acid; ((3-(2-Amino-2- dioxoethyl)-l-((l ,l'-biphenyl)-2-ylmethyl)-2-methyl-lH-ind- ol-4-yl)oxy)acetic acid methyl ester; ((3- (2-Amino- 1 ,2-dioxoethy I)- 1 -(( 1 , 1 '-bipheny l)-3 -y lmethyI)-2-methy I- 1 H-i- ndol-4-yl)oxy)acetic acid; ((3-(2-Amino-l,2-dioxoethy])-l -((l,l'-biphenyl)-3-ylmethyl)-2-methyl-lH-indol-4-yl)oxy)ace tic acid methyl ester; ((3-(2-Amino- 1 ,2-dioxoethyl)-l -(( 1 , 1 '-biphenyl)-4-ylmethyl)-2-methyl- 1 H-i- ndol-4- yl)oxy)acetic acid; ((3-(2-Amino-l,2-dioxoethyl)-l-((l, -biphenyl)-4-ylmethyI)-2-methyl-l H-i- ndol- 4-yl)oxy)acetic acid methyl ester; ((3-(2-Amino-l,2-dioxoethyl)-l-((2,6-dichlorophenyl)methyI)- 2- methyl-l H-i- ndoI-4-yl)oxy)acetic acid; ((3-(2-Amino-l ,2-dioxoethyl)-l-((2,6- dichlorophenyl)methyl)-2-methyl-lH-i- ndol-4-yl)oxy)acetic acid methyl ester; ((3-(2-Amino-l ,2- dioxoethy l)-l -(4(-fluorophenyl)methyl)-2-methyl-l H-indol-4-yl)oxy)acetic acid; ((3-(2 -Amino- 1,2- dioxoethyl))-l -(4(-fluorophenyl)methyl)-2-methyl-l H-indo- l-4-yl)oxy)acetic acid methyl ester; ((3- (2-Amino- 1 ,2-dioxoethyl)-2-methyl- 1 -(( 1 -naphthalenyl)methyl)- 1 H-indol-4-yl)oxy)acetic acid; ((3 -(2- Amino-l ,2-dioxoethyl)-2 -methyl- l-((l-naphthalenyl)methyl)-lH-indol-4-yl)oxy)acetic acid methyl ester; ((3-(2-Amino- 1 ,2-dioxoethyl)- 1 -((3-chlorophenyl)methyl)-2 -ethyl- 1 H-indol— 4-yl)oxy)acetic acid; ((3-(2-Amino-l ,2-dioxoethyl)-l-((3-chlorophenyl)methyl)-2-ethyl-lH-indol� � 4-yl)oxy)acetic acid methyl ester; ((3-(2-Amino-l ,2-dioxoethyl>l-((l,l'-biphenyl)-2-ylmethyl)-2-ethyl-lH-i n- dol-4- yl)oxy)acetic acid; ((3-(2-Amino- 1 ,2-dioxoethyl)- 1 -(( 1 , 1 '-bipheny I)-2-ylmethyl)-2-ethyl- 1 H-in- dol-4- yl)oxy)acetic acid methyl ester; ((3-(2-amino- 1 ,2-dioxoethyl)- 1 -(( 1 , 1 '-biphenyl)-2-ylmethyl)-2-propyl- lH-i- ndol-4-yl)oxy)acetic acid; ((3-(2-amino-l,2-dioxoethyl)-l -((l,r-biphenyl)-2-ylmethyl)-2- propyl-l H-i- ndol-4-yl)oxy)acetic acid methyl ester; ((3-(2-Amino-l ,2-dioxoethyl)-2-cyclopropyl-l- (phenylmethyl)- 1 H-indol-4-y l-)oxy)acetic acid; ((3-(2-Amino- 1 ,2-dioxoethyl)-2-cyclopropyl- 1 - (phenylmethyl)- lH-indol-4-yl-)oxy)acetic acid methyl ester; ((3-(2-Amino-l,2-dioxoethyl)-l-((l , l '- biphenyl)-2-ylmethyl>2-cyclopropyl-lH-indol-4-yl)oxy)acet ic acid; ((3-(2-Amino-l ,2-dioxoethyl)- 1 - ((1 , -biphenyl)-2-ylmethyl)-2-cyclopropyl-lH-indol-4-yl)oxy)aceti c acid methyl ester; 4-((3-(2-

Amino-l,2-dioxoethyl)-2-ethyl-l -(phenylmethyl)-lH-indol-5-yl)oxy-)butanoic acid; 4-((3-(2-Amino- l ,2-dioxoethyl)-2-ethyl-l -(phenylmethyl)-lH-indol-5-yl)oxy-) butanoic acid tert-butyl ester, or pharmaceutically acceptable salts, solvates, prodrug derivatives, racemates, tautomers, or optical isomers thereof.

(0371) In certain embodiments, PLA2G2A inhibitors for use in the current invention are

1 H-indole-3-glyoxylamide compounds having the structure:

[0373] wherein: each X is independently oxygen or sulfur; Ri is selected from groups (a), (b), and (c) wherein:

[0374] (a) is C7-C20 alkyl, C7-C20 alkenyl, C7-C20 alkynyl, carbocyclic radical, or heterocyclic radical;

[0375] (b) is a member of (a) substituted with one or more independently selected non- interfering substituents; and

[0376] (c) is the group— (L)— Rgo, wherein— (L)— is a divalent linking group of 1 to 12 atoms selected from carbon, hydrogen, oxygen, nitrogen, and sulfur;

[0377] wherein the combination of atoms in— (L)— are selected from the group consisting of (i) carbon and hydrogen only, (ii) sulfur only, (in) oxygen only, (iv) nitrogen and hydrogen only, (v) carbon, hydrogen, and sulfur only, and (vi) and carbon, hydrogen, and oxygen only; and where Rg ₀ is a group selected from (a) or (b); R ₂ is selected from the group consisting of hydrogen, halo, C,-C ₃ alkyl, C ₃ -C ₄ cycloalkyl, C3-C4 cycloalkenyl,— O— (C C ₂ alkyl),— S— <C,-C ₂ alkyl), and a non-interfering substituent having a total of 1 to 3 atoms other than hydrogen; R4 and R ₅ are independently selected from the group consisting of hydrogen, a non-interfering substituent, and the group— (L„)— (acidic group), wherein— (L _a >— is an acid linker having an acid linker length of 1 to 4; provided that at least one of R4 and R ₅ is— (L _a >— {acidic group); ¾ and R ₇ are each independently selected from the group consisting of hydrogen, non-interfering substituents, carbocyclic radicals, carbocyclic radicals substituted with non-interfering substituents, heterocyclic radicals, and heterocyclic radicals substituted with non-interfering substituents; and pharmaceutically acceptable salts, solvates, prodrug derivatives, racemates, tautomers, or optical isomers thereof.

[0378] In certain embodiments, PLA2G2A inhibitors for use in the current invention are methyl ester prodrug derivatives of lH-indole-3-glyoxylamide compounds having the structure:

[0380] wherein: both X are oxygen;

[0381] R| is selected from the group consisting of:

[0383] wherein Ri ₀ is a radical independently selected from halo, -Cio alkyl, Ci-Cio alkoxy,— S— (Ci-Cio alkyl), and CpCio haloalkyl, and t is a number from 0 to 5; R ₂ is selected from the group consisting of halo, cyclopropyl, methyl, ethyl, and propyl; ¾ and R5 are independently selected from the group consisting of hydrogen, a non-interfering substituent, and -— (L„)— (acidic group), wherein— (L _a )— is an acid linker; provided that the acid linker— (L _a )— for R4 is selected from the group consisting of:

[0385] provided that the acid linker— (L„)— for R ₅ is selected from the group consisting

[0387] wherein and Rgs are each independently selected from the group consisting of hydrogen, Ci-Cjo alkyl, aryl, Ci-Cio alkaryl, Ci-Cio aralkyl, carboxy, carbalkoxy, and halo; provided that at least one of R4 and R ₅ must be— (L _a )— (acidic group), and (acidic group) on— (L _a )— (acidic group) of R4 or R ₅ is selected from— C0 ₂ H,— S0 ₃ H, or— P(0)(OH) ₂ ; Re and R ₇ are each independently selected from the group consisting of hydrogen and non-interfering substituents, with the non-interfering substituents being selected from the group consisting of: C1-C alkyl, C2-C6 alkenyl, C ₂ -C ₆ alkynyl, C7-C12 aralkyl, C7-C12 alkaryl, C3-C8 cycloalkyl, C ₃ -Cg cycloalkenyl, phenyl, toluoyl, xylenyl, biphenyl, Q-Ce alkoxy, C ₂ -C ₆ alkenyloxy, C2-C ₆ alkynyloxy, C ₂ -Ci ₂ alkoxyalkyi, C ₂ - Ci2 alkoxyalkyloxy, C2-C12 alkylcarbonyl, C ₂ -Cn alkylcarbonylamino, C ₂ -C12 alkoxyamino, C2-C ₁ 2 alkoxyaminocarbonyl, C2-C12 alkylamino, C C ₆ alkylthio, C2-C ₁ 2 alkylthiocarbonyl, Ci-C ₆

alkylsulfinyl, Ci-C ₆ alkylsulfonyl, C ₂ -C ₆ haloalkoxy, Ci-C ₆ haloalkylsulfonyl, C ₂ -C ₆ haloalkyl, Ci-C ₆ hydroxyalkyi,— C(0)0(Ci-C ₆ alkyl),— (CH ₂ )„— O— (Ci-Cs alkyl), benzyloxy, phenoxy, phenylthio, — (CONHSO2 R),— CHO, amino, amidino, bromo, carbamyl, carboxyl, carbalkoxy,— (€¾),,— CO2 H, chloro, cyano, cyanoguanidinyl, fluoro, guanidino, hydrazide, hydrazino, hydrazido, hydroxy, hydroxyamino, iodo, nitro, phosphono,— SO ₃ H, thioacetal, thiocarbonyl, and C -Ce carbonyl;

wherein n is from 1 to 8; and pharmaceutically acceptable salts, solvates, prodrug derivatives, racemates, tautomers, or optical isomers thereof.

[0388] In certain embodiments, PLA2G2A inhibitors for use in the present invention are

(acyloxy) alkyl ester prodrug derivatives of 1 H-indole-3-glyoxylamide compounds having the ^' structure:

[0390] wherein: both X are oxygen; R] is selected from the group consisting of:

[0393] wherein R| ₀ is a radical independently selected from halo, C _r Cio alkyl, C]-C _]0 alkoxy,— S— (Ci-Cio alkyl), and Ci-Qo haloalkyl, and t is a number from 0 to 5; R2 is selected from the group consisting of halo, cyclopropyl, methyl, ethyl, and propyl; R and R ₅ are independently selected from the group consisting of hydrogen, a non-interfering substituent, and— -(L _a )— (acidic group), wherein— (L _a )— is an acid linker; provided that the acid linker— (L _a )— for R4 is selected from the group consisting of:

[0394] —-o— cn ₂ ² -~„„ and

[0395] provided that the acid linker— (L„)— for R ₅ is selected from the group consisting of:

[0397] wherein Rg ₄ and Rgs are each independently selected from the group consisting of hydrogen, C1-C10 alkyl, aryl, CpCio alkaryl, C1-C1 ₀ aralkyl, carboxy, carbalkoxy, and halo; provided that at least one of R4 and R ₅ must be -(L _a )-(acidic group), and (acidic group) on -(L _a )-(acidic group) of R4 or R ₅ is selected from— C0 ₂ H,— S0 ₃ H, or— P(0)(OH>2 ; R« and R ₇ are each independently selected from the group consisting of hydrogen and non-interfering substituents, with the non- interfering substituents being selected from the group consisting of: Q-Ce alkyl, C2-Q alkenyl, C2-C6 alkynyl, C ₇ -C| ₂ aralkyl, C ₇ -C| ₂ alkaryl, C ₃ -C ₈ cycloalkyl, C ₃ -C ₈ cycloalkenyl, phenyl, toluoyl, xylenyl, biphenyl, Ci-C ₆ alkoxy, C ₂ -Ce alkenyloxy, C ₂ -Ce alkynyloxy, C ₂ -Ci ₂ alkoxyalkyl, C2-C12

alkoxyalkyloxy, C ₂ -Ci ₂ alkylcarbonyl, C2-C ₁₂ alkylcarbonylamino, C2-C12 alkoxyamino, C ₂ -Ci ₂ alkoxyaminocarbonyl, C ₂ -Q ₂ alkylamino, Ci-C ₆ alkylthio, C2-C12 alkylthiocarbonyl, C C _¾ alkylsulfinyl, C _r C ₆ alkylsulfonyl, C ₂ -C6 haloalkoxy, C]-C ₆ haloalkylsulfonyl, C ₂ -Ce haloalkyl, C|-Q hydroxyalkyl,— C(0)0(C,-C ₆ alkyl),— (CH ₂ ) _n — O— - (CrC ₆ alkyl), benzyloxy, phenoxy, phenylthio, — (CONHSO2 R),— CHO, amino, amidino, bromo, carbamyl, carboxyl, carbalkoxy,— (CH ₂ ) _n — C0 ₂ H, chloro, cyano, cyanoguanidinyl, fluoro, guanidino, hydrazide, hydrazino, hydrazido, hydroxy, hydroxyamino, iodo, nitro, phosphono,— S0 ₃ H, thioacetal, thiocarbonyl, and C1-C6 carbonyl;

wherein n is from 1 to 8; and pharmaceutically acceptable salts, solvates, prodrug derivatives, racemates, tautomers, or optical isomers thereof.

[0398] In certain embodiments, PLA2G2A inhibitors for use in the current invention are substituted tricyclics having the structure:

[0399]

[0400] wherein: R| is selected from the group consisting of— NHNH2 and— :NH ₂ ; 2 is selected from the group consisting of— OH and— 0(CH2) _m Rs ; wherein R ₅ is selected from the group consisting of H,— C0 ₂ H,— C0 ₂ (C,-C ₄ alkyl),— S0 ₃ H,— S0 ₃ (C ^' i-Q alkyl), tetrazolyl,— CN,— NH ₂ ,— NHSO2 Ri5,— CONHSO2 R15, phenyl, phenyl substituted with— C0 ₂ H or— C0 ₂ (C _r C ₄ )alkyl, and

[0402] wherein Ri and R ₇ are each independently selected from the group consisting of— OH,— (Ci-C4)alkyl; R, 5 j _s selected from the group consisting of— (CrC ₆ )alkyl and— CF ₃ ; and m is 1-3; R ₃ is selected from the group consisting of H,— 0(C|-C ₄ )alkyl, halo,— (C _r C ₆ )alkyl, phenyl, — <Ci-C ₄ )alkylphenyl, phenyl substituted with— (C _r C ₆ )alkyl, halo, or— CF ₃ ,— CH ₂ OSi(C _r C ₆ )alkyl, furyl, thiophenyl,— (C _r C ₆ )hydroxyalkyl, and— (CH ₂ ) _n Rg; wherein Rj is selected from the group consisting of H,— CONH ₂ ,— NR ⁹ Rio,— CN, and phenyl; wherein R and Rio are each independently— (Ci-C ₄ )alkyl or -phenyl(Ci-C ₄ )alkyl; and n is 1 to 8; R4 is selected from the group consisting of H,— (C ₅ -Ci4)alkyl,— (C3-Ci ₄ )cycloalkyl, pyridyl, phenyl, and phenyl substituted with — (Ci-C ₆ )alkyl, halo,— CF ₃ ,— OCF ₃ ,— (C,-C ₄ )alkoxy,— CN,— (C _r C ₄ )alkylthio, phenyl(C,- 5 C ₄ )alkyl,— (Ci-C ₄ )alkylphenyl, phenyl, phenoxy, or naphthyl; A is selected from the group consisting of phenyl and pyridyl wherein the nitrogen is at the 5-, 6-, 7-, or 8-position; Z is selected from the group consisting of cyclohexenyl, phenyl, pyridyl wherein the nitrogen is at the 1-, 2-, or 3-position, and a 6-membered heterocyclic ring having one heteroatom selected from the group consisting of sulfur and oxygen at the 1-, 2-, or 3-position and nitrogen at the 1 -, 2-, 3-, or 4- position, or wherein 10 one carbon on the heterocyclic ring is optionally substituted with =0; and wherein one of A or Z is a heterocyclic ring; and pharmaceutically acceptable salts, solvates, prodrug derivatives, racemates, tautomers, or optical isomers thereof.

[0403] In certain embodiments, PLA2G2A inhibitors for use in the current invention are substituted tricyclics having the structure:

I S [0404]

[0405] wherein: Z is selected from the group consisting of cyclohexenyl and phenyl; R ₂ 1 is a non-interfering substituent; R _t is— NHNH ₂ or— NH ₂ ; R ₂ is selected from the group consisting of — OH and— 0(CH ₂ ) _m R ₅ ; wherein R5 is selected from the group consisting of H,— C0 ₂ H,— CONH ₂ ,— C0 ₂ (C,-C ₄ alkyl),— S0 ₃ H,— S0 ₃ (C,-C ₄ alkyl), tetrazolyl,— CN,— NH ₂ ,— NHS0 ₂ R, 20 5,— CONHS0 ₂ R, 5, phenyl, phenyl substituted with— C0 ₂ H or— C0 ₂ (Ci-C ₄ )alkyl, and

O

[0406] ^P(R6R?)

[0407] wherein Re and R ₇ are each independently selected from the group consisting of— OH,— 0(Ci-C ₄ )alkyl; R| 5 is selected from the group consisting of— (Ci-C6)alkyl and— CF3 ; and m is 1-3; R ₃ selected from the group consisting of H,— 0(C|-C ₄ )alkyl, halo,— (C|-C ₆ )alkyl, phenyl,— (C _r C ₄ )alkylphenyl, phenyl substituted with— (C _r C ₆ )alkyl, halo, or— CF ₃ ,— CH ₂ OSi(Ci-C ₆ )alkyl, furyl, thiophenyl,— (Ci-C ₆ )hydroxyalkyl, and— (CH ₂ )„Rg; wherein Rg is selected from the ^{^} group consisting of H,— CONH ₂ ,— NR ₉ Ri ₀ ,— CN, and phenyl; R ₉ and R _]0 are each independently selected from the group consisting of H,— CF ₃ , phenyl,— (C _r C ₄ )alkyl,— (C _r C ₄ )alkylphenyl, and— phenyl(C|-C ₄ )alkyl; and n is 1 to 8; R4 is selected from the group consisting of H,— (C ₅ -Ci )alkyl,— (C ₃ -C ₁₄ )cycloalkyl, pyridyl, phenyl, phenyl substituted with— (Ci-Ce)alkyl; halo,— CF ₃ ,— OCF3,— (C,-C ₄ )alkoxy,— CN,— (C _r C ₄ )alkylthio,— phenyI(C,-C ₄ )alkyl,— <C,-C ₄ )alkylphenyl, phenyl, phenoxy and naphthyl; and pharmaceutically acceptable salts, solvates, prodrug derivatives, racemates, tautomers, or optical isomers thereof.

(0408] In certain embodiments, PLA2G2A inhibitors for use in the current invention are selected from the group consisting of: {9-[(phenyl)methyI]-5-carbamoylcarbazol~4-yl}oxyacetic acid; 9-benzyl-5,7-dimethoxy-l,2,3,4-tetrahydrocarbazole-4-carboxy lic acid hydrazide; 9-benzyl-5,7- dimethoxy- 1 ,2,3 ,4-tetrahydrocarbazole-4-carboxamide; [9-benzyl-4-carbamoy l-7-methoxy- 1,2,3,4- tetrahydrocarbazol-5-yl]oxyacetic acid; [9-benzyl-4-carbamoyl-7-methoxycarbazol-5-yl]oxyacetic acid; methyl[9-benzyl-4-carbamoyl-7-methoxycarbazoI-5-yl]oxyacetic acid; 9-benzyl-7-methoxy-5- cyanomethyloxy- 1 ,2,3,4-tetrahydrocarbazole-4-carboxamide; 9-benzyl-7-methoxy-5-( 1 H-tetrazol-5- yl-methyl)oxy)-l ,2,3,4-tetrahydr- ocarbazole-4-carboxamide; {9-[(phenyl)methyl]-5-carbamoyl-2- methyl-carbazoI-4-yl}oxyacetic acid; {9-[(3-fluorophenyl)methyl]-5-carbamoyl-2-methylcarbazol-4- yl}oxyacetic acid; {9-[(3-methylphenyl)methyl]-5-carbamoyl-2-methylcarbazol-4-y l}oxyac- etic acid; {9-[(phenyl)methyl]-5-carbamoyl-2-(4-trifluoromethylphenyl)- car- bazol-4-yl}oxyacetic acid; 9- benzyl-5-(2-methanesulfonamido)ethyloxy-7-methoxy- 1 ,2,3,4-tetrahydrocar- bazole-4-carboxamide; 9-benzyl-4-(2-methanesulfonamido) ethyloxy-2-methoxycarbazole-5-carboxamide; 9-benzyl-4-(2- trifluoromethanesulfonamido)ethyloxy-2-methoxycarbazole-5-c- arboxamide; 9-benzyl-5- methanesulfonamidoylmethyloxy-7-methoxy-l ,2,3,4-tetrahydrocarb- azole-4-carboxamide; 9-benzyl- 4-methanesulfonamidoylmethyloxy-carbazole-5-carboxamide; [5-carbamoyl-2-pentyl-9- (phenylmethyl)carbazol-4-yl]oxyacetic acid; [5-carbamoyl-2-( 1 -methylethyl)-9- (phenylmethyl)carbazol-4-yl]oxyacetic acid; [5-carbamoyl-9-(phenylmethyl)-2-[(tri(-l- methylethyl)silyl)oxymethy- l]carbazol-4-yl]oxyacetic acid; [5-carbamoyl-2-phenyl-9- (phenylmethyl)carbazol-4-yl]oxyacetic acid; [5-carbamoyl-2-(4-chlorophenyl)-9- (phenylmethyl)carbazol-4-yl]oxyacetic acid; [5-carbamoyl-2-(2-furyl)-9-(phenylmethyl)carbazol-4- yl]oxyacetic acid; [5-carbamoyl-9-(phenylmethyl)-2-[(tri(- 1 -methylethyl)silyl)oxymethyl]carbazol-4- yl]oxyacetic acid; {9-[(2-Fluorophenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacet ic acid; {9-[(2- trifluoromethylphenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyac etic acid; {9-[(2- benzylphenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid; {9-[(l-naphthyl)methyl]-5- carbamoyIcarbazol-4-yl}oxyacetic acid; {9-[(2-cyanophenyl)methyl]-5-carbamoylcarbazol-4- yl}oxyacetic acid; {9-[(3-cyanophenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyaceti c acid; {9-[(3,5- dimethylphenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid; {9-[(3-iodophenyl)methyl]-5- carbamoylcarbazol-4-yl}oxyacetic acid; {9-[(2-Chlorophenyl)methyl]-5-carbamoylcarbazol-4- yl}oxyacetic acid; {9-[(2,3-difluorophenyl)methyl]-5-carbamoylcarbazol-4-yl}oxy acetic acid; {9-

[(2,6-difluorophenyl)methyl]-5-carbamoylcarbazol-4-yl}oxy acetic acid; {9-[(2,6- dichlorophenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid; {9-[(2-biphenyl)methyl]-5- carbamoylcarbazol-4-yl} oxyacetic acid; {9-[(2-Biphenyl)methyl]-5-carbamoylcarbazol-4- yl} oxyacetic acid methyl ester; [9-Benzyl-4-carbamoyl-l ,2,3,4-tetrahydrocarbazol-5-yl]oxyacetic acid; {9-[(2-Pyridyl)methyl]-5-carbamoylcarbazol-4-yl }oxyacetic acid; {9-[(3-Pyridyl)methyl]-5- carbamoyIcarbazol-4-yl} oxyacetic acid; [9-benzyl-4-carbamoyl-8-methyl-l ,2,3,4-tetrahydrocarbazol- 5-yl]oxyacetic acid; [9-benzyl-5-carbamoyI- l-methylcarbazol-4-yl]oxyacetic acid; [9-benzyl-4- carbamoyl-8-fluoro-l ,2,3,4-tetrahydrocarbazol-5-yl]oxyacetic acid; [9-benzyl-4-carbamoyl-8-chloro- l ,2,3,4-tetrahydrocarbazol-5-yl]oxya- cetic acid; [5-carbamoyI-9-(phenyImethyl)-2-[[(propen-3- yl)oxy]methyl]carbazol-4-yl]oxyacetic acid; [5-carbamoyl-9-(phenylmethyl)-2- [(propyloxy)methyl]carbazol-4-yl]oxyaceti-c acid; 9-benzyl-7-methoxy-5-((carboxamidomethyl)oxy)- 1 ,2,3,4-tetrahydroca- rbazole-4-carboxamide; 9-benzyl-7-methoxy-5-cyanomethyloxy-carbazole-4- carboxamide; 9-benzyl-7-methoxy-5-((l H-tetrazol-5-yl-methyl)oxy)-carbazoIe-4-carboxami- de; 9- benzyl-7-methoxy-5-((carboxamidomethyl)oxy)-carbazole-4-carb oxamide; [9-Benzyl-4-carbamoyl- l ,2,3,4-tetrahydrocarbazole-5-yl]oxyacetic acid; {9-[(phenyl)methyl]-5-carbamoyl-2-methyl-carbazol- 4-yl} oxyacetic acid; {9-[(3-fluorophenyl)methyl]-5-carbamoyl-2-methylcarbazol-4-y l} oxyacetic acid; {9-[(3-methylphenyl)methyl]-5-carbamoyl-2-methylcarbazol-4-y l}oxyac- etic acid; {9- [(phenyl)methyl]-5-carbamoyl-2-(4-trifluoromethylphenyl)-car - bazol-4-yl }oxyacetic acid; 9-benzyl- 5-(2-methanesulfonamido)ethyloxy-7-methoxy- 1 ,2,3,4-tetrahydrocar- bazole-4-carboxamide; 9- benzyl-4-(2-methanesulfonamido)ethyloxy-2-methoxycarbazole-5 -carboxamide; 9-benzyl-4-(2- trifluoromethanesulfonamido)ethyloxy-2-methoxycarbazole-5-ca rboxamide; 9-benzyl-5- methanesulfonamidoylmethyloxy-7-methoxy-l ,2,3,4-tetrahydrocarb- azole-4-carboxamide; 9-benzyl- 4-methanesulfonamidoylmethyloxy-carbazole-5-carboxamide; [5-carbamoyl-2-pentyl-9- (phenylmethyl)carbazol-4-yl]oxyacetic acid; [5-caTbamoyl-2-(l -methylethyl)-9- (phenylmethyl)carbazoI-4-yl]oxyacetic acid; [5-carbamoyl-9-(phenylmethyl)-2-[(tri(-l - methylethyl)silyl)oxymethyl]carbazol-4-yl]oxyacetic acid; [5-carbamoyl-2-phenyl-9- (phenylmethyl)carbazol-4-yl]oxyacetic acid; [5-carbamoyl-2-(4-chlorophenyl)-9- (phenyimethyl)carbazol-4-yI]oxyacetic acid; [5-carbamoyl-2-(2-furyl)-9-(phenylmethyl)carbazol-4- yl]oxyacetic acid; [5-carbamoyl-9-(phenylmethyl)-2-[(tri(-l-methylethyl)silyl)o xyrnethyl]carbazol-4- yljoxyacetic acid; {9-[(3-fluorophenyl)methyl]-5-carbamoylcarbazol-4-yI}0xyacet ic acid; {9-[(3- chlorophenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid; {9-[(3-phenoxyphenyl)methyl]-5- carbamoylcarbazol-4-yl} oxyacetic acid; {9-[(2-Fluorophenyl)methyl]-5-carbamoylcarbazol-4- yl}oxyacetic acid; {9-[(2-trifluoromethylphenyl)methyI]-5-carbamoylcarbazol-4-y l}oxyacetic acid; {9-[(2-benzylphenyl)methy]]-5-carbamoylcarbazol-4-yl}oxyacet ic acid; {9-[(3- trifluoromethylphenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyac etic acid; {9-[(l -naphthyl)methyl]-5- carbamoylcarbazol-4-yl}oxyacetic acid; {9-[(2-cyanophenyl)methyl]-5-carbamoylcarbazoI-4- yl}oxyacetic acid; {9-[(3-cyanophenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyaceti c acid; {9-[(2- methylphenyl)methyl]-5-carbamoylcarbazol-4-yI} oxyacetic acid; {9-[(3-methylphenyl)methyl]-5- carbamoylcarbazol-4-yl} oxyacetic acid; {9-[(3,5-dimethylphenyl)methyl]-5-carbamoylcarbazol-4- - yl} oxyacetic acid; {9-[(3-iodophenyl)methyI]-5-carbamoyIcarbazol-4-yl}oxyacetic acid; {9-[(2- Chlorophenyl)methyI]-5-carbamoylcarbazol-4-yl}oxyacetic acid; {9-[(2,3-difluorophenyl)methyl]-5- carbamoylcarbazol-4-yl} oxyacetic acid; {9-[(2,6-difluorophenyl)methyl]-5-carbamoylcarbazol-4- yljoxyacetic acid; {9-[(2,6-dichlorophenyl)methyl]-5-carbamoylcarbazol-4-yl}oxy acetic acid; {9-[(3- trifluoromethoxyphenyl)methyl]-5-carbamoylcarbazol-4-yl} oxyacetic acid; {9-[(2-biphenyl)methyl]- 5-carbamoylcarbazol-4-yl} oxyacetic acid; {9-[(2-Biphenyl)methyl]-5-carbamoylcarbazol-4- yljoxyacetic acid methyl ester; [9-Benzyl-4-carbamoyl-l ,2,3,4-tetrahydrocarbazo]e-5-yl]oxyacetic acid; {9-[(2-Pyridyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid; {9-[(3-Pyridyl)methyl]-5- carbamoylcarbazol-4-yl} oxyacetic acid; [9-benzyl-4-carbamoyl-8-methyl- 1 ,2,3 ,4-tetrahydrocarbazol- 5-yl]oxyacetic acid; [9-benzyl-5-carbamoyl-l -methylcarbazol-4-yl]oxyacetic acid; [9-benzyl-4- carbamoyI-8-fluoro- 1 ,2,3,4-tetrahydrocarbazol-5-yl]oxyacetic acid; [9-benzyl-5-carbamoyI- 1 - fluorocarbazol-4-yl]oxyacetic acid; [9-benzyl-4-carbamoyl-8-chloro-l,2,3,4-tetrahydrocarbazol-5- yl]oxyacetic acid; [9-benzyl-5-carbamoyl-l-chlorocarbazol-4-yl]oxyacetic acid; [9- [(Cyclohexyl)methyl]-5-carbamoylcarbazol-4-yl]oxyacetic acid; [9-[(Cyclopentyl)methyl]-5- carbamoylcarbazol-4-yl]oxyacetic acid; [5-carbamoyl-9-(phenylmethyl)-2-(2-thienyl)carbazol-4- yljoxyacetic acid; [5-carbamoyl-9-(phenylmethyl)-2-[[(propen-3-yl)oxy]methy!]ca rbazol-4- yl]oxyacetic acid; [5-carbamoyl-9-(phenylmethyl)-2-[(propyloxy)methyl]carbazol- 4-yl]oxyacetic acid; 9-benzyl-7-methoxy-5-((carboxamidomethyl)oxy)-l ,2,3,4-tetrahydroca- rbazole-4-carboxamide; 9- benzyl-7-methoxy-5-cyanomethyloxy-carbazole-4-carboxamide; 9-benzyl-7-methoxy-5-(( 1 H-tetrazol- 5-yl-methyl)oxy)-carbazole-4-carboxami- de; 9-benzyl-7-methoxy-5-((carboxamidomethyl)oxy)- carbazole-4-carboxamide; [9-Benzyl-4-carbamoyl-l,2,3,4-tetrahydrocarbazole-5-yl]oxyac etic acid; (R,S)-(9-benzyl-4-carbamoyl-l-oxo-3-thia-l,2,3,4-tetrahydroc arbazol-5-yl)- oxyacetic acid; (R,S)-(9- benzyl-4-carbamoyl-3-thia-l,2,3,4-tetrahydrocarbazol-5-yl)ox yace- tic acid; 2-(4-oxo-5-carboxamido- 9-benzyl-9H-pyrido[3,4-b]indolyl)acetic acid chloride; N-benzyl- 1 -carbamoyl- 1-aza- 1 ,2,3, 4- tetrahydrocarbazoI-8-yl]oxyacetic acid; 4-methoxy-6-methoxycarbonyl- 10-phenylmethyl-6,7,8,9- tetrahydropyrid- o[ 1 ,2-a]indole; (4-carboxamido-9-phenylmethyl-4,5-dihydrothiopyrano[3,4-b]in dol- 5-yl)oxyacetic acid; 3,4-dihydro-4-carboxamidol-5-methoxy-9-phenylmethylpyrano[3, 4-b]indoIe; 2- [(2,9 bis-benzyl-4-carbamoyl-l,2,3,4-tetrahydro-betacarbolin-5-yl) oxy]acetic acid; 2-[4-oxo-5- carboxamido-9-(2-methylbenzyl)-9H-pyrido[3,4-b]indolyl]aceti c acid; 2-[4-oxo-5-carboxamido-9-(3- methylbenzyl)-9H-pyrido[3,4-b]indolyl]acetic acid; 2-[4-oxo-5-carboxamido-9-(4-methylbenzyl)-9H- pyrido[3,4-b]indolyl]acetic acid; 2-[4-oxo-5-carboxamido-9-(4-tert-butylbenzyl)-9H-pyrido[3,4- b]indoIyl]acetic acid; 2-[4-oxo-5-carboxamido-9-pentafluorobenzyl-9H-pyrido[3,4-b]i ndolyl]acetic acid; 2-[4-oxo-5-carboxamido-9-(2-fluorobenzyl)-9H-pyrido[3,4-b]in dolyl]a-cetic acid; 2-[4-oxo-5- carboxamido-9-(3-fluorobenzyl)-9H-pyrido[3,4-b]indolyl]aceti c acid; 2-[4-oxo-5-carboxamido-9-(4- fluorobenzyl)-9H-pyrido[3,4-b]indolyl]a-cetic acid; 2-[4-oxo-5-carboxamido-9-(2,6-difluorobenzyl)- 9H-pyrido[3,4-b]indolyl]acetic acid; 2-[4-oxo-5-carboxamido-9-(3,4-difluorobenzyl)-9H-pyrido[3,4- b]indolyl]acetic acid; 2-[4-oxo-5-carboxamido-9-(2,5-di luoroben2yl)-9H-pyrido[3,4-b]indolyl]ace- tic acid; 2-[4-oxo-5-carboxamido-9-(3,5-dif]uorobenzyl)-9H-pyrido[3,4- b]in- dolyljacetic acid; 2-[4- oxo-5-carboxamidp-9-(2,4-difluorobenzyl)-9H-pyrido[3,4-b]ind olyl]ace- tic acid; 2-[4-oxo-5- carboxamido-9-(2,3-difluorobenzyl)-9H-pyrido[3 ₎ 4-b]in- dolyljacetic acid; 2-[4-oxo-5-carboxamido- 9-[2-(trifluoromethy])benzyl]-9H-pyrido[3,4-b]indolyl]acetic acid; 2r[4-oxo-5-carboxamido-9-[2- (trifluoromethyl)benzyl]-9H-pyrido[3,4-b]indolyl]acetic acid; 2-[4-oxo-5-carboxamido-9-[3- (trifluoromethyl)benzyl]-9H-pyrido[3,4-b]indolyl]acetic acid; 2-[4-oxo-5-carboxamido-9-[4- (trifluoromethyl)benzyl]-9H-pyrido[3,4-b]indolyl]acetic acid; 2-[4-oxo-5-carboxamido-9-[3,5- bis(trifluororriethyl)benzyl]-9H-pyrido[3,4-b-]indolyl]aceti c acid; 2-[4-oxo-5-carboxamido-9-[2,4- bis(trifluoromethyl)benzyl]-9H-pyrido[3,4-b-]indolyl]acetic acid; 2-[4-oxo-5-carboxamido-9-(a- methylnaphthyl)-9H-pyrido[3,4-b]indolyl]acetic acid; 2-[4-oxo-5-carboxamido-9-(b-methylnaphthyl)- 9H-pyrido[3,4-b]indolyl]acetic acid; 2-[4-oxo-5-carboxamido-9-(3,5-dimethylbenzyl)-9H-pyrido[3,4- b]indolyl]ace- tic acid; 2-[4-oxo-5-carboxamido-9-(2,4-dimethylbenzyl)-9H-pyrido[3,4- b]indolyl]acetic acid; 2-[4-oxo-5-carboxamido-9-(2-phenylbenzyl)-9H-pyrido[3,4-b]ir idolyl]acetic acid; 2-[4-oxo-5-carboxamido-9-(3-phenylbenzyl)-9H-pyrid0[3,4-b]in dolyl]acetic acid; 2-[4-oxo-5- carboxamido-9-(4-phenylbenzyl)-9H-pyrido[3,4-b]indolyl]aceti c acid; 2-[4-oxo-5-carboxamido-9-( 1 - fIuorenylmethy)-9H-pyrido[3,4-b]indolyl-]acetic acid; 2-[4-oxo-5-carboxamido-9-(2-fluoro-3- methylbenzyl)-9H-pyrido[3,4-b]indoly- l]acetic acid; 2-[4-oxo-5-carboxamido-9-(3-benzoylbenzyl)- 9H-pyrido[3 ,4-b] indoly l]acetic acid; 2-[4-oxo-5-carboxamido-9-(2-phenoxybenzyl)-9H-pyrido[3 ,4- b]indolyl]- acetic acid; 2-[4-oxo-5-carboxamido-9-(3-phenoxybenzyl)-9H-pyrido[3,4-b]i ndolyl]acetic acid; 2-[4-oxo-5-carboxamido-9-(4-phenoxybenzyl)-9H-pyrido[3,4-b]i ndolyl]- acetic acid; 2-[4-oxo- 5-carboxamido-9-[3-[2-(fluorophenoxy)benzyl]]-9H-pyrido[3,4- b]indolyl]acetic acid; 2-[4-oxo-5- carboxamido-9-[3-[4-(fluorophenoxy)benzyl]]-9H-pyrido[3,4-b] indolyl]acetic acid; 2-[4-oxo-5- carboxamido-9-[2-fluoro-3-(trifluoromethyI)benzyl]-9H-pyrido [3-,4-b]indoIyl]acetic acid; 2-[4-oxo-5- carboxamido-9-[2-fluoro-4-(trifluoromethyl)ben2yl]-9H-pyrido [3-,4-b]indolyl]acetic acid; 2-[4-oxo-5- carboxamido-9-[2-fluoro-5-(trifluoromethyI)ben2yl]-9H-pyrido [3-,4-b]indolyI]acetic acid; 2-[4-oxo-5- carboxamido-9-[3-fluoro-5-(trifluoromethyl)benzyl]-9H-pyrido [3-,4-b]indolyl]acetic acid; 2-[4-oxo-5- carboxamido-9-[4-fluoro-2-(trifluoromethyl)benzyl]-9H-pyrido [3-,4-b]indolyl]acetic acid; 2-[4-oxo-5- carboxamido-9-[4-fluoro-3-(trifluoromethyl)benzyl]-9H-pyrido [3-,4-b]indolyl]acetic acid; 2-[4-oxo-5- carboxamido-9 2-fluorcH6-(trifluoromethyl)ben2yl]-9H-pyrido[3-,4-b]indolyl ]acetic acid; 2-[4-oxo-5- carboxamido-9-(2,3,6-trifluoroben2yI)-9H-pyrido[3,4-b]indoly l]- acetic acid; 2-[4-oxo-5- carboxamido-9-(2,3,5-trifluorobenzyl)-9H-pyrido[3,4-b]indoly l]- acetic acid; 2-[4-oxo-5- carboxamido-9-(2,4,5-trifluorobenzyI)-9H-pyrido[3,4-b]indoly l]- acetic acid; 2-[4-oxo-5- carboxamido-9-(2,4,6-trifluorobenzyl)-9H-pyrido[3,4-b]indoly l]- acetic acid; 2-[4-oxo-5- carboxamido-9-(2,3,4-trifluorobenzyl)-9H-pyrido[3 ₎ 4-b]indolyl]- acetic acid; 2-[4-oxo-5- carboxamido-9-(3,4 ₅ 5-trifluorobenzyl)-9H-pyrido[3,4-b]indolyl]- acetic acid; 2-[4-oxo-5- carboxamido-9-[3-(trifluoromethoxyl)benzyl]-9H-pyrido[3,4-b] in- dolyl]acetic acid; 2-[4-oxo-5- carboxamido-9-[4-(trifIuoromethoxyl)benzyl]-9H-pyrido[3,4-b] indolyl]acetic acid; 2-[4-oxo-5- carboxamido-9-[4-methoxy(tetrafluoro)benzyl]-9H-pyrido[3,4-b ]indoIyl]acetic acid; 2-[4-oxo-5- carboxamido-9-(2-methoxybenzyl)-9H-pyrido[3,4-b]indolyI]acet ic acid; 2-[4-oxo-5-carboxamido-9- (3-methoxybenzyl)-9H-pyrido[3,4-b]indolyl]- acetic acid; 2-[4-oxo-5-carboxamido-9-(4- methoxybenzyl)-9H-pyrido[3,4-b]indoIyl]acetic acid; 2-[4-oxo-5-carboxamido-9-(4-ethylbenzyl)-9H- pyrido[3,4-b]indolyl]ac- etic acid; 2-[4-oxo-5-carboxamido-9-(4-isopropylbenzyl)-9H-pyrido[3,4- b]indolyl]acetic acid; 2-[4-oxo-5-carboxamido-9-(3,4,5-trimethoxybenzyl)-9H-pyrido[ 3,4-b]indolyl- ]acetic acid; 2-[4-oxo-5-carboxamido-9-(3,4-methylenedioxybenzyl)-9H-pyrid o[3,4-b]indolyl]acetic acid; 2-[4-oxo-5-carboxamido-9-(4-methoxy-3-methylbenzyl)-9H-pyrid o[3,4-b]indolyl]acetic acid; 2- [4-oxo-5-carboxamido-9-(3,5-dimethoxybenzyl)-9H-pyrido[3,4-b ]indolyl]ac- etic acid; 2-[4-oxo-5- carboxamido-9-(2,5-dimethoxybenzyl)-9H-pyrido[3,4-b]- indolyl]acetic acid; 2-[4-oxo-5- carboxamido-9-(4-ethoxybenzyl)-9H-pyrido[3,4-b]indolyl]aceti c acid; 2-[4-oxo-5-carboxamido-9- (cyclphexyl methyl)-9H-pyrido[3,4-b]indolyl]acetic acid; 2-[4-oxo-5-carboxamido-9- (cyclopentylmethyl)-9H-pyrido[3,4-b]indolyl]acetic acid; 2-[4-oxo-5-carboxamido-9-ethyl-9H- pyrido[3,4-b]indolyl]acetic acid; 2-[4-oxo-5-carboxamido-9-(l -propyl)-9H-pyrido[3,4-b]indoIyl]acetic acid; 2-[4-oxo-5-carboxamido-9-(2-propyl)-9H-pyridci[3,4-b]indolyl ]acetic acid; 2-[4-oxo-5- carboxamido-9-(l -butyl)-9H-pyrido[3,4-b]indolyl]acetic acid; 2-[4-oxo-5-carboxamido-9-(2-butyl)- 9H-pyrido[3 ,4-b]indolyl]acetic acid; 2-[4-oxo-5 -carboxamido-9-isobutyI-9H-pyrido[3 ,4- b]indolyl]acetic acid; 2-[4-oxo-5-carboxamido-9-[2-( 1 -phenylethyl)]-9H-pyridd[3,4-b]indolyl]acetic acid; 2-[4-oxo-5-carboxamido-9-[3-(l-phenylpropyl)]-9H-pyrido[3,4- b]indolyl]ace- tic acid; 2-[4-oxo- 5-carboxamido-9-[4-(l -phenylbutyl)]-9H-pyrido[3,4-b]ind- olyljacetic acid; 2-[4-oxo-5-carboxamido- 9-(l -pentyl)-9H-pyrido[3,4-b]indolyl]acetic acid; 2-[4-oxo-5-carboxamido-9-(l-hexyl)-9H-pyrido[3,4- b]indolyl]acetic acid; 4-[(9-benzyl-4-carbamoyl-l,2,3,4-tetrahydrocarbazol-6-yl)oxy ]butyric acid; 3- [(9-benzyl-4-carbamoyl-l,2,3,4-tetrahydrocarbazol-6-yl)oxy]p ropyl- phosphonic acid; 2-[(9-ben2yl-4- carbamoyl-l,2,3,4-tetrahydrocarbazol-6-yl)oxy]methylbenzoic acid; 3-[(9-benzyl-4-carbamoyl-7-n- octyl-l,2,3,4-tetrahydrocarbazol-6-yl-)oxy]propylphosphonic acid; 4-[(9-benzyl-4-carbamoyl-7-ethyl- l ,2,3,4-tetrahydrocarbazol-6-yl)oxy]buty- ric acid; 3-[(9-benzyl-4-carbamoyl-7-ethyl-l , 2,3,4- tetrahydrocarbazol-6-yl-)oxy]propylphosphonic acid; 3-[(9-benzyl-4-carbamoyl-7-ethyl-l, 2,3,4- tetrahydrocarbazol-6-yl)oxy]propylphosphonic acid; (S)-(+)-4-[(9-benzyl-4-carbamoyl-7-ethyl- l,2,3,4-tetrahydrocarbazol-6-yl)-oxy]butyric acid; 4-[9-benzyI-4-carbamoyl-6-(2-cyanoethyl)-l ,2,3,4- tetrahydrocarbazol-6-yl]-oxybutyric acid; 4-[9-benzyl-4-carboxamido-7-(2-phenylethyl)-l,2,3,4- tetrahydrocarbazoI-6— yljoxybutyric acid; 4-[9-benzyl-4-carboxamidocarbazol^6-yl]oxybutyric acid; methyl 2-[(9-benzyl-4-carbamoyl-l,2,3,4-tetrahydrocarbazol-6-yl)oxy ]methylbenzoa- te; 4-[9-benzyI- 4-carbamoyl-7-(2-cyanoethyl)-l,2,3,4-tetrahydrocarbazol-6— yljoxybutyric acid; 9-benzyl-7- methoxy-5-cyanomethyloxy-l,2,3,4-tetrahydrocarbazole-4-carbo xa- mide; [9-benzyl-4-carbamoyI-8- methyl-carbazoIe-5-yi]oxyacetic acid; and [9-benzyl-4-carbamoyl-carbazole-5-yl]oxyacetic acid, or pharmaceutically acceptable salts, solvates, prodrug derivatives, racemates, tautomers, or optical isomers thereof.

[0409] In certain embodiments, a PLA2G2A inhibitor for use in the present invention is ((3-(2- Amino- l ,2-dioxoethyl)-2-ethyl-l-(phenylmethyl)-lH-indol-4-yl)oxy)a- cetic acid, also referred to herein as compound A-001. Compound A-001, which is also referred to in the art as S-5920 or LY315920, has the structure:

[0411] competitively inhibits PLA2G2A.

[0412] In certain other embodiments, a PLA2G2A inhibitor for use in the present invention is [[3-(2-Amino- 1 ,2-dioxoethyl)-2-ethyl-l -(phenylmethyl)- 1 H-indol-4-yl]oxy]acetic acid methyl ester, also referred to herein as compound A-002. Compound A-002 has the structure:

[0414] Compound A-002, which is sometimes referred to in the art as S-3013 or LY333013, is a prodrug form of A-001 that is rapidly absorbed and hydrolyzed to A-001 following administration to a subject.

[0415] In certain other embodiments, a PLA2G2A inhibitor for use in the present invention is {9-[(phenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, also referred to herein as compound A-003 or LY433771. Compound A-003 has the structure:

[0417] In still other embodiments, a PLA2G2A inhibitor for use in the present invention is ((3-(2-amino- 1 ,2-dioxoethyl)-2-methyl- 1 -(phenylmethyl)- 1 H-indoI-4-yl)oxy acetic acid N- morpholino ethyl ester, also referred to herein as compound 421079. Compound 421079 has the structur

[0419] Like A-002, compound 421079 is a prodrug of A-001.

[0420] Alternative indole-based PLA2G2A inhibitors may be selected, for example, from compounds disclosed in U.S. Pat. No. 6,451 ,839 (Bach), which is expressly incorporated by reference herein in its entirety. Non-limiting compounds of this type have a structure represented by formula (IV) or a pharmaceutically acceptable salt, solvate, or prodrug derivative thereof:

[0421] [0422] wherein; R _\ is selected from groups (a), (b) and (c) wherein;

[0423] (a) is C ₇ -C ₂₀ alkyl, C ₇ -C ₂₀ haloalkyl, C ₇ -C ₂₀ alkenyl, C -C ₂₀ alkynyl, carbocyclic radical, or heterocyclic radical, or

[0424] (b) is a member of (a) substituted with one or more independently selected non- interfering substituents; or

[0425] (c) is the group— (Li)— R ; where,— (Lj)— is a divalent linking group of 1 to 8 atoms and Ru is a group selected from (a) or (b);

[0426] R2 is hydrogen, or a group containing 1 to 4 non-hydrogen atoms;

[0427] R ₃ is -— (L ₃ )— Z, where— (L ₃ )— is a divalent linker group selected from a bond or a divalent group selected from:

[0428]

[0429] Z is selected from a group represented by the formulae,

[0431] wherein, X is oxygen or sulfur; Y is— NH ₂ , Ci -C alkyl,— CF ₃ ,— CONH ₂ or— CH ₂ Z where Z is F, CI, Br, or I;

[0432] R4 and R ₅ each independently selected from hydrogen, a non-interfering substituent, or the group,— (L _a )-(acidic group), where— (L _a )— , is a divalent acid linker having an acid linker length of 1 to 8; provided that at least one of R4 and R5 must be the group,— (L _a )-(acidic group);

[0433] R<s and R ₇ are each independently selected from hydrogen, non-interfering substituent, carbocyclic radical, carbocyclic radical substituted with non-interfering substituent(s), heterocyclic radical, and heterocyclic radical substituted with non-interfering substituent(s).

[0434] In some embodiments of compounds according to formula (IV): R ₂ is hydrogen, Q -C ₄ alkyl, C ₂ -C alkenyl,— O— (C, -C ₃ alkyl),— S— <C, -C ₃ alkyl),— C ₃ -C ₄ cycloalkyl— CF ₃ , halo, — N0 _{2 l} — CN, or— S0 ₃ .

[0435] In some embodiments of compounds according to formula (IV): the acid linker group,— (L _a )— , for R4 is selected from a group represented by the formula:

[0437] where Q ₂ is selected from the group— <CH ₂ >— ,— O— ,— NH— ,— C(0>— , and — S— , and each R40 is independently selected from hydrogen, Cj -C ₈ alkyl, aryl, Ci -C ₈ aikaryl, C| -Cg alkoxy, aralkyl, and halo.

[0438] In some embodiments of compounds according to formula (IV): the acid linker,— (L„)— , for R ₅ is selected from a group represented by the formulae consisting of:

[0440] wherein R ₅ , , R ₅₅ , R ₅₆ and R ₅₇ are each independently hydrogen, Ci -Cg alkyl, Q - Cg haloalkyl, aryl, C|. -Cg alkoxy, or halo.

[0441] In some embodiments of compounds according to formula (IV): only one of R4 and R ₅ is the group,— (L _a )-(acidic group) and wherein the (acidic group) is selected from the group:

-5-tetrazolyl,— SO H,

[0443] where Rso is a metal or Q-Cg alkyl and R^ is an organic substituent or— CF3 .

[0444] Suitably, the (acidic group) is— C0 ₂ H.

[0445] In some embodiments of compounds according to formula (IV): for R ₃ , Z is the represented by the formula:

[0446]

[0447] and the linking group— (L ₃ )— is a bond.

[0448] In some embodiments of compounds according to formula (IV): for R« the non- interfering substituent is hydrogen, Ci-C ₈ alkyl, C ₂ -C ₈ alkenyl, C2 -C ₈ alkynyl, C ₇ -Cn aralkyl, C7-C12 alkaryl, C ₃ -C ₈ cycloalkyl, C ₃ -C ₈ cycloalkenyl, phenyl, to!ulyl, xylenyl, biphenyl, Ci-C ₈ alkoxy, C ₂ -C ₈ alkenyloxy, C ₂ -C ₈ alkynyloxy, C2-C12 a!koxyalkyl, C2 -C12 alkoxyalkyloxy, C2-C ₁ 2 alkylcarbonyi, C ₂ - C ₁ 2 alkylcarbonylamino, C2-C12 alkoxyamino, C2-G ₁₂ alkoxyaminocarbonyl, C ₁ -C12 alkylamino, C ₁ -C6 alkylthio, C ₂ -C| ₂ alky lth iocarbonyl, Ci-Cg alkylsulfinyl, Ci-Cg alkylsulfonyl, C2-G ₈ haloalkoxy, Ci-C ₈ haloalkylsulfonyl, C ₂ -C ₈ haloalkyl, C,-C ₈ hydroxyalkyl,— C(0)0(C|-C ₈ alkyl),— (CH ₂ )„— O— (C,- C ₈ alkyl), benzyloxy, phenoxy, phenylthio,— (CONHSO2 R),— CHO, amino, amidino, bromo, carbamyl, carboxyl, carbalkoxy,— (CH ₂ )„— C0 ₂ H, chloro, cyano, cyanoguanidinyl, fluoro, guanidino, hydrazide, hydrazino, hydrazido, hydroxy, hydroxyamino, iodo, nitro, phosphono,— S0 ₃ H, .thioacetal, thiocarbonyl, or carbonyl; where R is Ci -C ₈ alkyl and n is from 1 to 8.

[0449] In some embodiments of compounds according to formula (IV): for R) the divalent linking group— (L|)— is selected from a group represented by the formulae (Vila), (Vllb), (VIIc), (Vlld), (Vile), and (Vllf):

[0451] O (Vllb),

[0456] where Qi is a bond or any of the divalent groups Vila, Vllb, VIIc, Vlld, and Vile and Rio is independently— H, Q -8 alkyl, C| -8 haloalkyl or O -8 alkoxy.

[0457] Suitably, the linking group— (L,)— of R, is— (CH ₂ >— or— (CH ₂ — CH ₂ >— .

[0458] In some embodiments of compounds according to formula (IV): for R| the group Rn is a substituted or unsubstituted carbocyclic radical selected from the group consisting of cycloalkyl, cycloalkenyl, phenyl, spiro[5.5]undecanyl, naphthyl, norbornanyl, bicycloheptadienyl, tolulyl, xylenyl, indenyl, stilbenyl, teφhenylyl, diphenylethylenyl, phenyl-cyclohexenyl, acenaphthylenyl, and anthracenyl, biphenyl, bibenzylyl and related bibenzylyl homologues represented by the formula (a):

[0460] where n is a number from 1 to 8.

[0461] In illustrative examples of this type, for R| the combined group— (Li)— R| i is selected from the groups:

[0463] where Rn is a radical independently selected from halo, Ci -Cio alkyl, Ci -Cio alkoxy,— S— (Q -Ci ₀ alkyl), and Q -Cio haloalkyl, Ci -C| ₀ hydroxyalkyl and t is a number from 0 to 5 and u is a number from 0 to 4.

[0464] In some embodiments, for R| the radical R, i is a substituted or unsubstituted heterocyclic radical selected from pyrrolyl, pyrrolodinyl, piperidinyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, phenylimidazolyl, triazolyl, isoxazolyl, oxazolyl, thiazolyl, thiadiazolyl, indolyl, carbazolyl, norharmanyl, azaindolyl, benzofuranyl, dibenzofuranyl, dibenzothiophenyl, indazolyl, imidazo(l,2-A)pyridinyl, benzotriazolyl, anth ^' ranilyl, 1,2-benzisoxazolyl, benzoxazolyl,

benzothiazolyl, purinyl, pyridinyl, dipyridylyl. phenylpyridinyl, benzylpyridinyl, pyrimidinyl, phenylpyrimidinyl, pyrazinyl, 1 ,3,5-triazinyl, quinolinyl, phthalazinyl, quinazolinyl,moφholino, thiomorpholino, homopiperazinyl, tetrahydrofuranyl, tetrahydropyranyl, oxacanyl, 1 ,3-dioxolanyl, 1 ,3- dioxanyl,)l ,4-dioxanyl, tetrahydrothiopheneyl, pentamethylenesulfadyl, 1 ,3-dithianyl, 1 ,4-dithian l, 1 ,4-thioxanyl, azetidinyl, hexamethyleneiminium, heptamethyleneiminium, piperazinyl or quinoxaltnyl.

[0465] In specific embodiments, compounds according to formula (IV) are in the form of a sodium salt and/or in the form of an ester prodrug.

[0466] In other embodiments, the indole compounds disclosed in U.S. Pat. No. 6,451 ,839 (Bach) are represented by the formula (V), or a pharmaceutically acceptable salt, solvate, or prodrug derivative thereof:

[0467] [0468] wherein; R _\ 6 is selected from hydrogen and Ci -C ₈ alkyl, Q -C ₈ alkoxy, Ci -Cg alkylthio Ci -C ₈ haloalkyl, d -C ₈ hydroxyalkyl, and halo;— (L )— is a divalent group selected from:

[0470] where R40 , R41 , R42 _> and R43 are each independently selected from hydrogen, Q C ₈ alkyl; R22 is selected from hydrogen, methyl, ethyl, propyl, isopropyl, cyclopropyl,— F,— CF ₃ , - CI,—Br, or— O— CH ₃ ; and R, 3 is C, -C ₈ alkyl, C, -C ₈ alkoxy, phenyl, halophenyl,— S— (C| -C ₈ alkyl), Q -C ₈ haloalkyl, Q -C ₈ hydroxyalkyl, and halo; and t is an integer from 0 to 5.

[0471] In specific embodiments, the indole compounds disclosed in U.S. Pat. No.

6,451,839 (Bach) are represented by the formula (CI):

|0473] Still other indole-based PLA2G2A inhibitors may be selected from compounds disclosed in U.S. Pat. Nos. 6,635,670 (Lin) and 6,706,752 (Lin) and in U.S. Pat. Appl. Pub. No. 2003/0153770 (Lin), which are expressly incorporated by reference herein in their entirety.

Representative compounds of this type have a structure represented by formula (VI) or a pharmaceutically acceptable salt, _^ solvate, or prodrug derivative thereof: [0474]

[0475] wherein; Ri is selected from groups (a), (b) and (c) wherein;

[0476] (a) is C ₇ -C ₂₀ alkyl, C ₇ -C ₂₀ haloalkyl, C ₇ -C20 alkenyl, C? -C ₂₀ alkynyl, carbocyclic radical, or heterocyclic radical, or

[0477] (b) is a member of (a) substituted with one or more independently selected non- interfering substituents; or

[0478] (c) is the group— (Li)— R ; where,— (Li)— is a divalent linking group of 1 to 8 atoms and Rn is a group selected from (a) or (b);

[0479] R ₂ is hydrogen, or a group containing 1 to 4 non-hydrogen atoms plus any required hydrogen atoms;

[0480] R ₃ is— (L ₃ )— Z, where ^<L ₃ )— is a divalent linker group selected from a bond or a divalent group selected from:

[0482] Z is selected from a group represented by the formulae,

[0484] wherein, X is oxygen or sulfur; and R ₀ is selected from hydrogen, C| -Cj alkyl, aryl, Ci -Cg alkaryl, C| -C ₈ alkoxy, aralkyl and— CN;

[0485] R4 is the group, -(L _c )-(acylamino acid group); wherein -(L _c )-, is an acylamino acid linker having an acylamino acid linker length of 1 to 8; .

[0486] R ₅ is selected from hydrogen, a non-interfering substituent, or the group, -(L _a )- (acidic group); wherein -(L _a )-, is an acid linker having an acid linker length of 1 to 8; [0487] ¾ and R ₇ are selected from hydrogen, non- interfering substituent, carbocyclic radical, carbocyclic radical substituted with non-interfering substituent(s), heterocyclic radicals, and heterocyclic radical substituted with non-interfering substituent(s).

[0488] In some embodiments of compounds according to formula (VI): R ₂ is hydrogen, Ci -C ₄ alkyl, C ₂ -C ₄ alkenyl,— O— (C, -C ₃ alkyl),— S— (C, -C ₃ alkyl),— C ₃ -C ₄ cycloalkyl— CF ₃ , halo, — N0 ₂ ,— CN, or— S0 ₃ .

[0489] In some embodiments of compounds according to formula (VI): the acylamino linker group,— (L _c )— , for R4 is selected from a group represented by the formula:

[0491] where Q ₂ is selected from the group -^(CH ₂ )— , ,— NH— ,— C(O)— , and

— S— , and each R40 is independently selected from hydrogen, Ci -Cg alkyl, aryl, Ci -Cg alkaryl, Ci -C ₈ alkoxy, aralkyl, and halo.

[0492] In some embodiments of compounds according to formula (VI): the acylamino acid linker group, -(L _c )-, for R4 is a divalent group selected from:

or

[0494] where R40 , R41 , R42 . and R* ₃ are each independently selected from hydrogen, C] -

C ₈ alkyl.

[0495] In some embodiments of compounds according to formula (VI): the acid linker,— (L _a )— , for R ₅ is selected from a group represented by the formulae consisting of:

[0497] wherein R ₅₄ , R ₅₅ , K _$ t and R57 are each independently hydrogen, C| -Cg alkyl, C| - Cg haloalkyl, aryl, Ci -Cg alkoxy, or halo.

[0498J In some embodiments of compounds according to formula (VI): only one of R» and R ₅ is the group,— (L _a )-(acidic group) and wherein the (acidic group) is selected from the group:

[0500] where R«o is a metal or Ci -C ₈ alkyl and Rgi is an organic substituent or— CF ₃ .

[0501] In some embodiments of compounds according to formula (VI): for R ₃ , Z is the group represented by the formula:

[05021

[0503] and the linking group— (L ₃ )— is a bond and R* is hydrogen.

[0504] In some embodiments of compounds according to formula (VI): Z is the group represented by the formula: > '

[0505]

[0506] and the linking group -(L ₃ )- is a bond.

[0507] In some embodiments of compounds according to formula (VI): for R ₃ , Z is the group represented by the formula:

[0508]

[0509] and the linking group -(L ₃ )- is a bond.

[0510] Suitably, for Ri the non-interfering substituent is hydrogen, Ci -C» alkyl, C ₂ -Cg alkenyl, C ₂ -C ₈ alkynyl, C7 -C12 aralkyl, C ₇ -C12 alkaryl, C ₃ -C ₈ cycloalkyl, C ₃ -C ₃ cycloalkenyl, phenyl, tolulyl, xylenyl, biphenyl, C _\ -C ₈ alkoxy, C2 -C ₈ alkenyloxy, C ₂ -Cg alkynyloxy, C2 -C ₎₂ alkoxyalkyl, C2 -C ₁₂ alkoxyalkyloxy, C ₂ -C12 alkylcarbonyl, C ₂ -C| ₂ alkylcarbonylamino, C2 -C12 alkoxyamino, C ₂ -C12 alkoxyaminocarbonyl, Ci -C12 alkylamino, C| -C ₆ alkylthio, C ₂ -C12

alkylthiocarbonyl, Ci -C ₈ alkylsulfinyl, Ci -C ₈ alkylsulfonyl, C ₂ -C ₈ haloalkoxy, C| -C ₈

haloalkylsulfonyl, C ₂ -C ₈ haloalkyl, C, -C ₈ hydroxyalkyl,— C(0)0(C, -C ₈ alkyl),— (CH ₂ ) _n — O— (C.s- ub. l -C ₈ alkyl), benzyloxy, phenoxy, phenylthio,— (CONHS0 ₂ R),— CHO, amino, amidino, bromo, carbamyl, carboxyl, carbalkoxy,— (CH ₂ ) _n — C0 ₂ H, chloro, cyano, cyanoguanidinyl, fluoro, guanidino, hydrazide, hydrazino, hydrazido, hydroxy, hydroxyamino, iodo, nitro, phosphono,— S0 ₃ H, thioacetal, thiocarbonyl, or carbonyl; where n is from 1 to 8. [0511] In some embodiments of compounds according to formula (VI): for R| the divalent linking group— (Li)— is selected from a group represented by the formulae (la), (lb), (Ic), (Id), (Ie), and (If):

[0512] H ₂ (la),

[0513] — o— ■(lb),

[0514] — s (Ic),

N

[0515] H (W),

[0518] where Qi is a bond or any of the divalent groups la, lb, Ic, Id, and Ie and R _!0 is independently— H, Ci -8 alkyl, Ci -8 haloalkyl or Ci -8 alkoxy.

[0519] Suitably, the linking group— <L,)— of R, is— <CH ₂ )— or— <CH ₂ — CH ₂ )— .

[0520] In some embodiments of compounds according to formula (VI): the linking group - (Lii)- of R) I is a bond and Rn is— (CHj)m-R ¹² wherein m is an integer from 1 to 6, and R ¹² is a group represented b the formula:

[0523] wherein a, c, e, n, q, and t are independentl an integer from 0 to 2, R ¹³ and R ^H are independently selected from a halogen, Ci to Cs alkyl, Ci to C _¾ alkyloxy, Q to Cs alkylthio, aryl, heteroaryl, and Ci to C ₈ haloaikyl, .alpha, is an oxygen atom or a sulfur atom, L ⁵ is a bond,— (CH ₂ )v-,

— C=C— ,— CC— , ·, or— S— , v is an integer from 0 to 2, .beta, is— CH2— or— ( H h— ,

.gamma, is an oxygen atom or a sulfur atom, b is an integer from 0 to 3, d is an integer from 0 to 4, f, p, and w are independently an integer from 0 to 5, r is an integer from 0 to 7, and u is an integer from 0 to 4, or is (e) a member of (d) substituted with at least one substituent selected from the group consisting of d to C ₆ alkyl, Ci to C _s alkyloxy, C to C ₈ haloalkyloxy, Ci to Cg haloaikyl, aryl, and a halogen.

[0524] In some embodiments of compounds according to formula (VI): for K the group Ri i is a substituted or unsubstituted carbocyclic radical selected from the group consisting of cycloalkyl, cycloalkenyl, phenyl, spiro[5.5]undecanyl, naphthyl, norbomanyl, bicycloheptadienyl, tolulyl, xyl ^' enyl, indenyl, stilbenyl, terphenylyl, diphenylethylenyl, phenyl-cyclohexenyl,

acenaphthylenyl, and anthracenyl, biphenyl, bibenzylyl and related bibenzylyl homologues represented by the formula (a):

[0526] where n is a number from 1 to 8.

[0527] In illustrative examples of this type, for R] the combined group— (Li)— Ru is selected from the groups:

(cai)i-i-<\ /)— (CH ₂ )^2-

[0529] where Rn is a radical independently selected from halo, -Cio alkyl, C] -Cio alkoxy,— S— (d -C ₁₀ alkyl), and Ci -C _]0 haloalkyl, C\ -Cio hydroxyalkyl and t is a number from 0 to 5 and u is a number from 0 to 4.

[0530] In some embodiments, for Ri the radical R _n is a substituted or unsubstituted heterocyclic radical selected from pyrrolyl, pyrrolodinyl, piperidinyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, phenylimidazolyl, triazolyl, isoxazolyl, oxazolyl, thiazolyl, thiadiazolyl, indolyl, carbazolyl, norharmanyl, azaindolyl, benzofiiranyl, dibenzofuranyl, dibenzothiophenyl, indazolyl, imidazo(l,2-A)pyridinyl, benzotriazolyl, anthranilyl, 1,2-benzisoxazolyl, benzoxazolyl,

benzothiazolyl, purinyl, pyridinyl, dipyridylyl. phenylpyridinyl, benzylpyridinylv pyrimidinyl, phenylpyrimidinyl, pyrazinyl, 1 ,3,5-triazinyl, quinolinyl, phthalazinyl, quinazolinyl.morpholino, thiomoφholino, homopiperazinyl, tetrahydrofuranyl, tetrahydropyranyl, oxacanyl, 1,3-dioxolanyl, 1 ,3 dioxanyl, 1,4-dioxanyl, tetrahydrothiopheneyl, pentamethylenesulfadyl, 1,3-dithianyl, 1 ,4-dithianyl, 1,4-thioxanyl, azetidinyl, hexamethyleneiminium, heptamethyleneiminium, piperazinyl or quinoxalinyl.

[0531] In some embodiments of compounds according to formula (VI): R4 is the group - (L _c )-(acylamino acid group) and wherein the (acylamino acid group) is:

O C N

\

[0532] ^R 4b

[0533] and R ^4a is selected from the group consisting of H, (Ci -C ₆ )alkyl, (C, -C6)alkoxy, heteroaryl and aryl; and wherein NR ^4b is an amino acid residue of a natural or unnatural amino acid with the nitrogen atom being part of the amino group of the amino acid.

[0534] In specific embodiments, the indole compounds disclosed in U.S. Pat. Nos.

6,635,670 (Lin) and 6,706,752 (Lin) and in U.S. Pat. Appl. Pub. No. 2003/0153770 (Lin) are represented by formula (VII) or a pharmaceutically acceptable salt, solvate, or prodrug derivative thereof:

" (Rl3)t

[0535] (VII)

x

[0536] wherein Ι½ is selected from hydrogen, methyl, ethyl, propyl, isopropyl, cyclopropyl,— F,— CF ₃ ,—CI,—Br, or— O— CH ₃ ;

[0537] R ^a is hydrogen; and NR ^4b is an amino acid residue of a natural or unnatural amino acid with the nitrogen atom being part of the amino group of the amino acid, and -(L _c )- is a divalent group selected from:

[0539] where R40 , R41 , R 2 , and R43 are each independently selected from hydrogen or C| -C ₈ alkyl;

[0540] Ri 6 is selected from hydrogen, C, -C ₈ alkyl, Ci -C ₈ alkoxy, C, -C ₈ alkylthio C, -C ₈ haloalkyi, Ci -C ₈ hydroxyalkyl, and halo; and

[0541] Ri 3 is selected from hydrogen and d -C ₈ alkyl, Ci -C ₈ alkoxy,— S— (C _\ -C ₈ alkyl), Ci -C ₈ haloalkyi, Q -C ₈ hydroxyalkyl, phenyl, halophenyl, and halo, and t is an integer from 0 to 5:

[0542] In illustrative examples of indole compounds according to formula (VI) or (VII), the compounds are represented by the formulae (CI), (C2), (C3), (C4), (C5), (C6), (C7), (C8), (C9), (ClO) or (Cl l):

-86-

1

6

[0554] In specific embodiments, the indole compounds according to formula (VI) or (VII) are selected from: N-[2-[[3-(Aminooxoacetyl)-2 -ethyl- l-(phenylmethyl)- l H-indol-4- yl]oxy]acetyl]g!ycine; N-[2-[[3-(Aminooxoacetyl)-2-ethyl-l -(phenylmethyl)-l H-indoI-4— yl]oxy]acetyl]glycine methyl ester; N-[2-[[3-(Aminooxoacetyl)-2-ethyl-l -(p- henylmethyl)-l H-indol- 4-yI]oxy]acetyl]glycine; N-[2-[[3-(Aminooxoacetyl)-2- -ethyl- 1 -(phenylmethyl)- l H-indol-4- yl]oxy]acetyl]-L-alanine; N-[2-[[3-(Aminooxoacetyl)-2-ethyl-l -(phenylmethyl)- i H-indol-4- yl]oxy]acetyl]-L-alanine methyl ester; N-[2-[[3-(Aminooxoacetyl)-2-ethyl-l -(phenylmethyl)- l H- indol-4-yl]oxy]acetyl]-L-alanine; N-[2-[[3-(Aminooxoacetyl)-2-ethy- 1-1 -(phenylmethyl)- lH-indol-4- yl]oxy]acetyl]-L-leucine; N-[2-[[3-(Aminooxoacetyl)-2-ethyl- 1 -(phenylmethyl)- 1 H-indoI-4- yi]oxy]acetyl]-L-leucine methyl ester; N-[2-[[3-(AminooxoacetyI)-2-ethyl- 1 -(phenylmethyl)- 1H- indol-4-yl]oxy]acetyl]-L-leucine; N-[2-[[3-(Aminooxoacetyl)-2-ethy- 1- 1 -(phenylmethyl)- l H-indol-4- yl]oxy]acetyl]-L-aspartic acid; N-[2-[[3-(Aminooxoacetyl)-2-ethyl-l -(phenylmethyl)- l H-indol-4- yl]oxy]acet- yl]-L-aspartic acid dimethyl ester; N-[2-[[3-(Aminooxoacetyl)-2 -ethyl- l-(p- henylmethyl)-l H-indol-4-yl]oxy]acetyl]-L-aspartic acid; N-[2-[[3-( Aminooxoacetyl)-2 -ethyl- 1 - (phenylmethyl)-lH-indol-4-yl]oxy]acetyl]-L-phenylalanine; N-[2-[[3-(Aminooxoacetyl)-2-ethyl-l - (phenylmethyl)-lH- -indol-4-yl]oxy]acetyl]-L-phenylalanine methyl ester; N-[2-[[3- (Aminooxoacetyl)-2-ethyl- l -(phenylmethyl)- l H-indol-4-yl]oxy]acet- yl]-L-pheny!alanine; [2-[[3- (Aminooxoacetyl)-2-ethyl-l -(phenylmethyl)- ΙΗ-i- ndol-4-yl]oxy]acetamido]malonic acid; [2-[[3- (Aminooxoacetyl)-2-ethyl-l -(p- henylmethyl)-l H-indol-4-yl]oxy]acetamido]malonic acid dimethyl ester [2-[[3-( Aminooxoacetyl)-2 -ethyl- 1 -(phenylmethyl)- lH-indol-4-yl]oxy]acetamido]malonic acid; N-[2-[[3-(Aminooxoacetyl)-2 -ethyl- 1 -(phenylmethyl)- Ι Η-in- dol-4-yl]oxy]acetyl]-L-valine; N-[2-[[3- (Aminooxoacetyl)-2-ethyl-l -(phenyl- methyl)- l H-indol-4-yl]oxy]acetyl]-L-valine methyl ester; N-[2- [[3-(Aminooxoacetyl)-2-ethyl-l -(phenylmethyl)-l H-indol-4-yl]oxy]acetyl]-L-valine; N-[2-[[3- (Aminooxoacetyl)-2-ethyl-l -(phenylmethyl)- l H-indol— 4-yl]oxy]acetyl]-L-isoleucine; N-[2-[[3- (Aminooxoacetyl)-2-ethyl- l -(phenyl- methyl)- l H-indol-4-yl]oxy]acetyI]-L-isoleucine methyl ester; and N-[2-[[3-(Aminooxoacetyl)-2-ethyl- l -(phenyImethyl)-lH-indol-4-yl]oxy]acetyl]-L-isoleucine.

[0555] Still other indole-based PLA2G2A inhibitors may be selected, for example, from compounds disclosed in U.S. Pat. Appl. Pub. No. 2004/0029948 (Harper), which is hereby incorporated by reference herein in its entirety. Non-limiting compounds of this type have a structure represented by formula (VIII) or a pharmaceutically acceptable salt, solvate, or prodrug derivative thereof:

[0556]

[0557] wherein; Ri is selected from groups (a), (b) and (c) wherein;

[0558] (a) is C ₇ -C ₂ o alkyl, G ₇ -C ₂₀ haloalkyl, C ₇ -C ₂₀ alkenyl, C ₇ -C ₂₀ alkynyl, carbocyclic radical, or heterocyclic radical, or

[0559] (b) is a member of (a) substituted with one or more independently selected non- interfering substituents; or

[0560] (c) is the group— (Li)— Rn ; where,— (Lj)— is a divalent linking group of 1 to 8 atoms and R| _† is a group selected from (a) or (b);

[0561] R ₂ is hydrogen, or a group containing 1 to 4 non-hydrogen atoms plus any required hydrogen atoms;

[0562] R3 is— (Lj)— Z, where— (L ₃ )— is a divalent linker group selected from a bond or a divalent group selected from:

[0564] Z is selected from a group represented by the formulae,

[0565]

(0566) wherein, X is oxygen or sulfur; and R _a is selected from hydrogen; Ci -Cg alkyl, aryl, Ct -C ₈ alkaryl, Q -C ₈ alkoxy, aralkyl and— CN;

[0567] R4 is the group, -(L _h )-(hydroxyfunctional amide); wherein -(L _h )-, is a

hydroxyfunctional amide linker having a hydroxyfunctional amide linker length of 1 to 8;

[0568] R ₅ is selected from hydrogen, a non-interfering substituent, or the group, -(L _a )- (acidic group); wherein -(L _a )-, is an acid linker having an acid linker length of 1 to 8;

[0569] R _¾ and R are selected from hydrogen, non-interfering substituent, carbocyclic radical, carbocyclic radical substituted with non-interfering substituent(s), heterocyclic radicals, and heterocyclic radical substituted with non-interfering substituent(s).

[0570] In some embodiments of compounds according to formula (VIII): R ₂ is hydrogen, C, -C ₄ alkyl, C ₂ -C ₄ alkenyl,— O- C -C ₃ alkyl),— S— (C, -C ₃ alkyl),— C ₃ -C ₄ cycloalkyl— CF ₃ , halo,— N0 ₂ ,— CN, or— S0 ₃ .

[0571] In some embodiments of compounds according to formula (VIII): the

hydroxyfunctional amide,— (L _h )— , for R4 is selected from a , group represented by the formula:

[0573] where Q ₂ is selected from the group— (CH ₂ )— ,— O— ,— NH— ,— C(O)— , and — S— , and each is independently selected from hydrogen, Q -Cg alkyl, aryl, Cj -Cg alkaryl, Ci -Cg alkoxy, aralkyl, and halo.

[0574] In some embodiments of compounds according to formula (VIII); the

hydroxyfunctional amide group, -(L _h )-, for R4 is a divalent group selected from:

[0576] where R40 , R41 , R« , and R4 ₃ are each independently selected from hydrogen, Cg alkyl.

[0577] In some embodiments of compounds according to formula (VIII): the acid linker, — (L _a )— , for R ₅ is selected from a group represented by the formulae consisting of:

[0579] wherein R ₅₄ , R ₅₅ , R ₅ 6 and R ₅₇ are each independently hydrogen, Ci -C ₈ alkyl, Ci - C ₈ haloalkyl, aryl, Ci -Cg alkoxy, or halo.

[0580] In some embodiments of compounds according to formula (VIII): R5 is the group, — (L _a )-(acidic group) and the (acidic group) is selected from the group:

[0582] where Rgo is a metal or Ci -Gs alkyl and Rgi is an organic substituent or— CF ₃

[0583] In some embodiments of compounds according to formula (VIII): for R3 , Z is group represented by the formula:

[0584]

[0585] and the linking group -(L ₃ )- is a bond; and R _a is hydrogen, methyl, ethyl, propyl, isopropyl, phenyl or benzyl.

[0586] In some embodiments of compounds according to formula (VIII): for R ₃ , Z is the group represented by the formula:

[0588] and the linking group -(L ₃ )- is a bond; and R _a is hydrogen.

[0589] In some embodiments of compounds according to formula (VIII): Z is the group represented by the formula:

[0591] and the linking group -(L ₃ )- is a bond.

[0592] In some embodiments of compounds according to formula (VIII): for R ₃ , Z is the group represented by the formula:

[0593]

[0594] and the linking group -(L ₃ )- is a bond.

[0595] Suitably, for the non-interfering substituent is hydrogen, Cj -Cg alkyl, C ₂ -C ₈ alkenyl, C ₂ -Cg alkynyl, C ₇ -Ci ₂ aralkyl, C ₇ -C ₎₂ alkaryl, C ₃ -C ₈ cycloalkyl, C ₃ -C ₈ cycloalkenyl, phenyl, tolulyl, xylenyl, biphenyl, Ci -Cg alkoxy, C ₂ -Cg alkenyloxy, C ₂ -C ₈ alkynyloxy, C ₂ -C| ₂ alkoxyalkyl, C ₂ -C; ₂ alkoxyalkyloxy, C ₂ -C ₎₂ alkylcarbonyl, C ₂ -Cn alkylcarbonylamino, C ₂ -C ₎₂ alkoxyamino, C ₂ -C| ₂ alkoxyaminocarbonyl, Ci -C] ₂ alkylamino, Ci -C6 alkylthio, C ₂ -Ci ₂ alkylthiocarbonyl, Ci -Cg alkylsulfmyl, Ci -Cg alkylsulfonyl, C ₂ -Cg haloalkoxy, Ci -Cg

haloalkylsulfonyl, C ₂ -C ₈ haloalkyl, C, -C ₈ hydroxyalkyl,— C(0)0(C, -C ₈ alkyl),— <CH ₂ ) _n — O— (C.s- ub.l-Cg alkyl), benzyloxy, phenoxy, phenylthio,— (CONHS0 ₂ R),— CHO, amino, amidino, bromo, carbamyl, carboxyl, carbalkoxy,— (CH ₂ )„— C0 ₂ H, chloro, cyano, cyanoguanidinyl, fluoro, guanidino, hydrazide, hydrazino, hydrazido, hydroxy, hydroxyamino, iodo, nitro, phosphono,— S0 ₃ H, thioacetal, thiocarbonyl, or carbonyl; where n is from 1 to 8.

[0596] In some embodiments of compounds according to formula (VIII): for R| the divalent linking group— (Li)— is selected from a group represented by the formulae (la), (lb), (Ic), (Id), (Ie), and (If):

[0597] ¾ (i _a)) [0598] O (ft),

[0599] (Ic), [0600] (Id),

[0603] where Qi is a bond or any of the divalent groups la, lb, Ic, Id, and Ie and R _t0 is independently— H, Ci -8 alkyl, Ci -8 haloalkyl or C] -8 alkoxy.

[0604] Suitably, the linking group— <Li>— of R, is— (CH ₂ )— or— (CH ₂ — CH ₂ — .

[0605] In some embodiments of compounds according to formula (VIII): the linking group -(Li i)- of Ri i is a bond and Rn is— (CH ₂ )m-R ¹² wherein m is an integer from 1 to 6, and R ¹² is a group represented by the formula:

[0608] wherein a, c, e, n, q, and t are independently an integer from 0 to 2, R ¹³ and R ¹⁴ are independently selected from a halogen, d to C ₈ alkyl, C| to Cg alkyloxy, Ci to C ₈ alkylthio, aryl, heteroaryl, and C| to Ct haloalkyl, .alpha, is an oxygen atom or a sulfur atom, L ⁵ is a bond,— (CH ₂ )v-,

— C=C— ,— CC— ,— O— , or— S— , v is an integer from 0 to 2, .beta, is— CH ₂ — or— (CH ₂ ) ₂ — ,

.gamma, is an oxygen atom or a sulfur atom, b is an integer from 0 to 3, d is an' integer from 0 to 4, f, p, and w are independently an integer from b to 5, r is an integer from 0 to 7, and u is an integer from 0 to 4, or is (e) a member of (d) substituted with at least one substituent selected from the group consisting of Q to C ₆ alkyl, C| to Cg alkyloxy, d to C ₈ haloalkyloxy, Ci to Cg haloalkyl, aryl, and a halogen.

[0609] In some embodiments of compounds according to formula (VIII): for Ri the group

Rii is a substituted or unsubstituted carbocyclic radical selected from the group consisting of cycloalkyl, cycloalkenyl, phenyl, spiro[5.5]undecanyl, naphthyl, norbornanyl, bicycloheptadienyl, tolulyl, xylenyl, indenyl, stilbenyl, terphenylyl, diphenylethylenyl, phenyl-cyclohexenyl,

acenaphthylenyl, and anthracenyl, biphenyl, bibenzylyl and related bibenzylyl homologues represented by the formula (a):

[0611] where n is a number from 1 to 8.

[0612] In illustrative examples of this type, for R _\ the combined group— (L|)— Ru is selected from the groups:

[0614] where Ru is a radical independently selected from halo, Ci -Ci ₀ alkyl, Ci -C _!0 alkoxy,— S— (Ci -Cio alkyl), and Ci -Cjo haloalkyl, C, -Cio hydroxyalkyl and t is a number from 0 to 5 and u is a number from 0 to 4.

[0615] In some embodiments, for R _t the radical Ru is a substituted or unsubstituted heterocyclic radical selected from pyrrolyl, pyrrolodinyl, piperidinyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, phenylimidazolyl, triazolyl, isoxazolyl, oxazolyl, thiazolyl, thiadiazolyl, indolyl, carbazolyl, norhar anyl, azaindolyl, benzofuranyl, dibenzofuranyl, dibenzothiophenyl, indazolyl, imidazo(l,2-A)pyridinyl, benzotriazolyl, anthranilyl, 1 ,2-benzisoxazolyl, benzoxazolyl,

benzothiazolyl, purinyl, pyridinyl, dipyridylyl. phenylpyridinyl, benzylpyridinyl, pyrimidinyl, phenylpyrimidinyl, pyrazinyl, 1,3,5-triazinyl, quinolinyl, phthalazinyl, quinazolinyl,mo holino, thiomo holino, homopiperazinyl, tetrahydrofuranyl, tetrahydropyranyl, oxacanyi, 1,3-dioxolanyl, 1 ,3- dioxanyl, 1 ,4-dioxanyl, tetrahydrothiopheneyl, pentamethylenesulfadyl, 1,3-dithianyl, 1,4-dithianyl, 1,4-thioxanyl, azetidinyl, hexamethyleneiminium, heptamethyleneiminium, piperazinyl or quinoxalinyl.

[0616] In some embodiments of compounds according to formula (VI): R, is the group - (L _h )-(hydroxyfunctional amide group) and wherein the (hydroxyfunctional amide group) is:

O

^■ C II N

\

[0617] ^R 4b

[0618] and R ^4a is s independently selected from the group consisting of OH, (C| - C ₆ )alkoxy, (C ₇ -Q -4)alkaryloxy, (C ₂ -C ₈ )alkenyloxy, (C ₇ -C _{i ) aralkyloxy, (C ₇ -C ₁₄ )aralkenyloxy and aryloxy; and wherein R ^4b is independently selected from the grbup consisting of H, (Ci -C6)alkyl, arylalkyl, heteroaryl and aryl.

[0619] In specific embodiments, the indole compounds disclosed in U.S. Pat, Appl. Pub.

No. 2004/0029948 are represented by formula (IX) or a pharmaceutically acceptable salt, solvate, or prodrug derivative thereof:

[0621] wherein R ₂₂ is selected from hydrogen, methyl, ethyl, propyl, isopropyl, cyclopropyl,— F,— CF ₃ ,— CI,— Br, or— O— CH ₃ ;

[0622] R ^a is independently selected from the group consisting of OH, (Ci -C ₆ )alkoxy, (C ₇ -Ci4)alkaryloxy, (C ₂ -C ₈ )alkenyloxy, (C ₇ -CM) aralkyloxy, (C ₇ -Cujaralkenyloxy and aryloxy; and R ^b is H, (Ci -C ₆ )alkyl, arylalkyl, heteroaryl or aryl and -(L _h )- is a divalent group selected from:

[0623]

[0625] where R40 , ¾i , R42 _» and R43 are each independently selected from hydrogen or Ci

-Cg alkyl;

[0626] R, 6 is selected from hydrogen, d -C ₈ alkyl, C, -C ₈ alkoxy, C, -Cg alkylthio G, -C ₈ haloalkyl, C| -Cg hydroxyalkyl, and halo;

[0627] R, 3 is selected from hydrogen and Ci -Cg alkyl, C, -Cg alkoxy,— S— (Q -C ₈ alkyl), Ci -Cg haloalkyl, C _\ -C ₈ hydroxyalkyl, phenyl, halophenyl, and halo, and t is an integer from 0 to 5.

[0628] Non-limiting examples of the compounds according to formula (IX) may be selected from: 2-[[3-(Aminooxoacetyl)-2-ethyl-l -(phenylmethyl)-l H-indol-4-yl]oxy]-N- (hydroxy)acetamide; 2-[[3-(Aminooxoacetyl)-2-ethyl- l-(phenylmethyl)-l H-indol-4- -yl]oxy]-N- (methyloxy) acetamide; 2-[[3-(Aminooxoacetyl)-2-ethyl-l-phenylm- ethyl)- l H-indol-4-yl]oxy]-N- (methyl)-N-(methyloxy)acetamide; 2-[[3-(Aminooxoacetyl)-2-emyl-l -(phenylmethyl)- l H-indol-4- yl]oxy]-N-(hyd- roxy)-N-(methyl)acetamide; 2-[[3-(Aminooxoacetyl)-2-ethyl- 1 -(phenylmethyl)- -1 H- indol-4-yl]oxy]-N-(ethyloxy) acetamide; 2-[[3-(Aminooxoacetyl)-2-ethyl- -1 -(phenylmethyl)- 1 H- indol-4-yl]oxy]-N-(2-propenyloxy) acetamide; 2-[[3-(Aminooxoacetyl)-2-ethyl-l -(phenylmethyl)-l H- indoI-4-yl]oxy]-N-(hydroxy)-N-(2-propyl)acetamide; 2-[[3-(Aminooxoacetyl)-2-ethyl- 1 - (phenylmethyl)-lH-indol-4-yl]oxy]-N-(tert-butyloxy)acetamide ; 2-[[3-(Aminooxoacetyl)-2- -ethyl-1 - (phenylmethyl)-l H-indol-4-yl]oxy]-N-[2-(methyl)propyloxy]acetamide; 2-[[3-(Aminooxoacetyl)-2- ethyl-1 -(phenylmethyl)- l H-indol-4-yl]oxy]-N-(phenylmethyloxy) acetamide; 2-[[3- ( Aminooxoacetyl)-2 -ethyl- 1 -phenylmethyl)— lH-indol-4-yl]oxy]-N-(methyl)-N-(phenylmethyloxy) acetamide; 2-[[3-(Aminooxoacetyl)-2-ethyI-l -(phenylmethyl)-l H-indol-4-yl]oxy]-N-(phenyloxy) acetamide; 2-[[3-(Aminooxoacetyl)-2-ethyl-l H-(phenylmethyl)-l H-ind- ol-4-yl]oxy]-N-(methyl)-N- (phenyloxy) acetamide; 2-[[3-(Aminooxoacetyl)-2— ethyl-1 -(phenylmethyl)- 1 H-indol-4-yl]oxy]-N- (cyclohexyl)-N-(hydroxy)acetamide; and 2-[[3-(2-Amino-2-oxoethyl)-2 -ethyl- 1 -(phenylmethyl)- 1 H- indol-4-yl- ]oxy]-N-(hydroxy)acetamide. _;

[0629] In specific embodiments of the indole compounds represented by formula (VIII) or (IX), the compounds are represented by the formulae (CI ), (C2), (C3), (C4), (C5), (C6), (C7), (C8), (C9), (C 10), (C l l), (C 12), (C13), (C14) or (C15):

- 100-

- 102-

- 103 -

[0645] or pharmaceutically acceptable salts or prodrugs thereof.

[0646] Still other PLA2G2A inhibitors are described for example in U.S. Pat. Nos.

6,472,389, 6,384,041, 6,703,385, 6,768,545, 6, 673,781, 6,756,376, EP839806, EP846687, EP950661 , EP846687, WO92/08712, WO97/03951, W097/38966, W098/24437, W099/59999, WO2000/07590, WO98/05332, W098/18464, W098/24756, W098/24794, W099/21546, W099/21545, W09921559, WO2000/07591, WO2002/50030, WO2002/50028, WO2002/57231 , WO2001/49662,

WO2002/79154, WO2003/01482, WO2003/016722, WO2002/50029, WO2002/50034,

WO2002/00641, WO2002/12249, WO2003/048139, JP832514, JP325154, JP0045740, and in Reid, R (Current Medicinal Chemistry, 2005, 12, 301 1-3026), which are expressly incorporated herein by reference in their entirety. [0647] The above examples are merely provided as illustrations of the types of inhibitors that may be used in the present invention, and as such are not meant to be limiting. One of ordinary skill in the art will recognize that a variety of other PLA2G2A inhibitors may be used.

3.5 Screening methods

[0648] The present invention also features methods of screening for agents that inhibit

PLA2G2A. Candidate agents encompass numerous chemical classes, though typically they are organic molecules, preferably small organic compounds having a molecular weight of more than 50 and less than about 2,500 Dalton. Candidate agents comprise functional groups necessary for structural interaction with proteins, particularly hydrogen bonding, and typically include at least an amine, carbonyl, hydroxyl or carboxyl group, preferably at least two of the functional chemical groups. The candidate agent often comprises cyclical carbon or heterocyclic structures or aromatic or polyaromatic structures substituted with one or more of the above functional groups. Candidate agents are also found among biomolecules including, but not limited to: peptides, saccharides, fatty acids, steroids, purines, pyrimidines, derivatives, structural analogues or combinations thereof.

[0649] Small (ηοή-peptide) molecule modulators of PLA2G2A are particularly advantageous. In this regard, small molecules are desirable because such molecules are more readily absorbed after oral administration, have fewer potential antigenic determinants, or are more likely to cross the cell membrane than larger, protein-based pharmaceuticals.

[0650] Alternatively , libraries of natural compounds in the form of bacterial, fungal, plant and animal extracts are available or readily produced. Additionally, natural or synthetically produced libraries and compounds are readily modified through conventional chemical, physical and biochemical means, and may be used to produce combinatorial libraries. Known pharmacological agents may be subjected to directed or random chemical modifications, such as acylation, alkylation, esterification, amidification, etc. to produce structural analogues.

[0651] Screening may also be directed to known pharmacologically active compounds and chemical analogues thereof.

[0652] Screening for PLA2G2A inhibitor agents can be achieved by any suitable assay. The ability of candidate agents to inhibit can be measured using any suitable assay. For example, candidate agents may inhibit or reduce expression of the PLA2G2A gene and thus assays that measure the level of PLA2G2A transcripts (e.g., northern analysis, reverse transcriptase polymerase chain reaction etc.) or the level of expressed PLA2G2A protein produced in or secreted by the cell (e.g., enzyme-linked immunosorbent assays (ELISA), chemiluminescent immunoassay (CLIA), immunohistochemistry etc.) Alternatively, PLA2G2A inhibitors can reduce or inhibit the functional activity of PLA2G2A, which catalyzes the hydrolysis of phospholipids at the sn-2 position yielding a free fatty acid and a lysophospholipid. The release of arachidonic acid from membrane phospholipids by SPLA2 enzymes such as PLA2G2A is believed to be a key step in the control of eicosanoid .

production within the cell. Several SPLA2 functional assays are known that measure this release. For example, the assay by Reynolds et al. can be employed (Reynolds et al, 1992), which uses the 1 ,2- dithio analog of diheptanoyl phosphatidylcholine that serves as a substrate for most PLA2s with the exception of cytosoiic PLA2. Upon hydrolysis of the thio ester bond at the sn-2 position by PLA2, free thiols are detected using DTNB (5,5-dithio-bis-(2-nitrobenzoic acid)). An embodiment of this assay ("sPLA ₂ assay kit") is sold commercially by Cayman Chemical Company, Ann Arbor, MI, USA). Other functional assays may measure the release of PGE2 (e.g., using an ELISA), as described for instance in the Examples.

[0653] The present invention further contemplates derivatizing an agent that tests positive for PLA2G2A inhibitor activity, and optionally formulating the derivatized agent with a

pharmaceutically acceptable carrier, to improve the efficacy of the agent for treating or preventing the adiposity-related condition(s).

3.6 PLA2G2A inhibitor derivatives and conjugates

[0654] The present invention also extends to conjugates and derivatives of the adiposity- modulating PLA2G2A inhibitors. For example, the PLA2G2A inhibitors may be conjugated with biological targeting agents that enable their activity to be restricted to particular cell types (e.g., immune cells such as macrophages, monocytes, dendritic cells, neutrophils T-cells, mast cells etc.). Such biological-targeting agents include substances (e.g., antibodies or antibody fragments) that are interactive with or bind to cell-specific surface antigens. In representative examples of this type, a

PLA2G2A inhibitor is conjugated with an agent (e.g., antibody or antibody fragment) that is immuno- interactive with an immune cell surface marker such as for example, a macrophage specific/selective surface marker (e.g., CD 14, CD68, CD 163 and or human epidermal growth factor module-containing mucin-like receptor 1 (EMR1 ), etc.), a monocyte specific/selective surface marker (e.g., 63D3, adipophilin, CD1 la, CDl lb, CD14, CD15, CD54, CD62L, CD300e, etc.), a T-cell specific/selective surface marker (e.g., CDl a, CDld, CD2, CD3, CD4, CD8, CD25, CD38, CD45RO, CD134, CD150, etc.) or a mast cell specific/selective surface marker (e.g., CD34, Ki-MCl and Ki-Ml P). The conjugate confers immune cell specificity or preference to the effects of the PLA2G2A inhibitor. Illustrative molecules of this type include a liposome that comprises an antibody or antibody fragment that is immuno-interactive with the immune cell specific/selective surface marker, and a PLA2G2A inhibitor. Alternatively, or in addition, a PLA2G2A inhibitor may be conjugated with an agent (e.g., antibodies or antibody fragments) that is interactive with or binds to an adipose tissue marker (e.g., S- 100), which targets the conjugate to adipose or fat deposits or organs or tissues where PLA2G2A is present. The conjugate may further comprise an ancillary agent that has a different beneficial function or additional inhibitor properties against PLA2 enzymes and proteins. [0655] The PLA2G2A inhibitor may include a property-modifying moiety for enhancing biological activity, prolonging blood circulation time, reducing immunogenicity, increasing aqueous solubility, and enhancing resistance to protease digestion. In some embodiments, the property- modifying moiety modifies the property of the PLA2G2A inhibitor so that it achieves a sufficient hydrodynamic size to prevent clearance by renal filtration in vivo. For example, a property-modifying moiety can be selected that is a polymeric macromolecule, which is substantially straight chain, branched-chain, or dendritic in form. Alternatively, a property-modifying moiety can be selected such that, in vivo, the PLA2 inhibitor will bind to a serum protein to form a complex, such that the complex thus formed avoids substantial renal clearance. The property-modifying moiety can be, for example, a lipid; a cholesterol group (such as a steroid); a carbohydrate or oligosaccharide; or any natural or synthetic protein, polypeptide or peptide that binds to a salvage receptor.

[0656J Exemplary property-modifying moieties that can be used, in accordance with the present invention, include an immunoglobulin Fc domain, or a portion thereof, or a biologically suitable polymer or copolymer, for example, a polyalkylene glycol compound, such as a polyethylene glycol or a polypropylene glycol. Other appropriate polyalkylene glycol compounds include, but are not limited to, charged or neutral polymers of the following types: dextran, polylysine, colominic acids or other carbohydrate based polymers, polymers of amino acids, and biotin derivatives.

[0657] Other examples of the property-modifying moiety, in accordance with the invention, include a copolymer of ethylene glycol, a copolymer of propylene glycol, a

carboxymethylcellulose, a polyvinyl pyrrolidone, a poly- 1 ,3-dioxolane, a poly- 1 ,3,6-trioxane, an ethylene/maleic anhydride copolymer, a polyaminoacid (e.g., polylysine), a dextran n-vinyl pyrrolidone, a poly n-vinyl pyrrolidone, a propylene glycol homopolymer, a propylene oxide polymer, an ethylene oxide polymer, a polyoxyethylated polyol, a polyvinyl alcohol, a linear or branched glycosylated chain, a polyacetal, a long chain fatty acid, a long chain hydrophobic aliphatic group, an immunoglobulin Fc domain or a portion thereof (see, for example, U.S. Pat. No. 6,660,843 (Feige)), a CH2 domain of Fc, an albumin (e.g., see, for example, U.S. Pat. No. 6,926,898 and U.S. Pat Appl.. Pub. No. 2005/0054051 (Rosen); and U.S. Pat. No. 6,887,470 (Bridon), or a transthyretin (TTR; see, for example, U.S. Pat. Appl. Pub. No. 2003/0195154; 2003/0191056 (Walker)).

[0658] Other embodiments of the property-modifying moiety, in accordance with the present invention, include peptide ligands or small (organic) molecule ligands that have binding affinity for a long half-life serum protein under physiological conditions of temperature, pH, and ionic strength. Examples include an albumin-binding peptide or small molecule ligand, a transthyretin- binding peptide or small molecule ligand, a thyroxine-binding globulin-binding peptide or small molecule ligand, an antibody-binding peptide or small molecule ligand, or another peptide or small molecule that has an affinity for a long half-life serum protein (see, e.g., U.S. Pat. No. 5,714,142 (Blaney) U.S. Pat. Appl. Pub. No. 2003/0069395 (Sato); U.S. Pat. No. 6,342,225 (Jones)). A "long half-life serum protein" is one of the hundreds of different proteins dissolved in mammalian blood plasma, including so-called "carrier proteins" (such as albumin, transferrin and haptoglobin), fibrinogen and other blood coagulation factors, complement components, immunoglobulins, enzyme inhibitors, precursors of substances such as angiotensin and bradykinin and many other types of proteins. The invention encompasses the use of any single species of pharmaceutically acceptable property-modifying moiety such as but not limited to, those described herein, or the use of a combination of two or more different half-life extending moieties, such as PEG and immunoglobulin Fc domain or a CH2 domain of Fc, albumin (e.g., HSA), an albumin-binding protein, transthyretin or TBG.

[0659] In some embodiments, the property-modifying moiety is polyethylene glycol

(PEG). For example, the PLA ₂ inhibitors can be made mono-PEGylated, di-PEGylated, or otherwise multi-PEGylated, by the process of reductive alkylation.

4. Compounds of Formula (IB) and compositions comprising them

In one aspect of the invention there is provided a compound of formula (IB):

[0660] wherein:

[0661] X is selected from the group consisting of:

[0662] CRR'C0 ₂ H, CRR'C0 ₂ C,^alkyl, CRR'-tetrazolyl, CRR'SOjH, CRR' P(0)(OH) ₂ , CRR' P(0)(OH)(OR"), CHRCH ₂ C0 ₂ H, CHRCH ₂ -tetrazolyl, CHRCH ₂ S0 ₃ H, CHRCH ₂ P(0)(OH) ₂₎ CHRCH ₂ P(0)(OH)(OR"), OP(0)(OH)R', NRS0 ₃ H, NRP(0)(OH) ₂ , NRP(0)(OH)(OR")

[0663] wherein R, R' and R" are independently selected from hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted acyl, optionally substituted arylalkyl, optionally substituted cycloalkylalkyl and optionally substituted heterocyclylalkyl, except that R" is not hydrogen; ,

[0664] Q is a group selected from formulae (a)-(g): [06

(a) (b) (c)

(d) (e) (f) (g) .

[0666] Rioo is optionally substituted cycloalkyl;

[0667] Z is a group selected from formulae (i)-(iv):

[0668] (i) -(CH ₂ ) _m -aa-(CH ₂ ) _n -B; or

[0669] (ii) -(CH ₂ ) _m -aa-(C¾) _n -A-(CH ₂ ) ₀ -B; or

[0670] (iii) -(CH ₂ ) _p -A-(CH ₂ ) _q -A'-(CH ₂ ) _r -B; or

[0671] (iv) -(CH ₂ ) _S -B;

[0672] wherein

[0673] m is 0 or 1 , n, o, p, q and r are independently selected from 0 to 15 and s is from 5 to 15,

[0674J aa is an amino acid side chain residue;

[0675] A and A' are independently selected from O, S, NH, NR, NHC(O), NRC(O), CH ₂ , CHR, CH H ₂ , C(O), C(0)0, C(0)NH, OC(O), and CH=CH, wherein R is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted arylalkyl, optionally substituted cycloalkylalkyl and optionally substituted heterocyclylalkyl;

[0676] B is selected from, hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted cycloalkyl, optionally substituted aryloxy, and optionally substituted heterocyclyloxy; optionally substituted cycloalkyloxy, C0 ₂ H; and [0677] wherein m, n, o, p, q, r, s, aa, A, A' and B are such that the longest continuous chain of atoms in a group of formula (i)-(iv) is from 5 to 15 atoms long;

[0678] or salt, derivative or prodrug thereof.

[0679] In particular embodiments of compounds of formula (IB), one or more of the following applies:

[0680] X is selected from CH ₂ C0 ₂ H and CH ₂ C0 ₂ C]^alkyl, especially CH ₂ C0 ₂ H, CH ₂ C0 ₂ CH ₃ and CH ₂ C0 ₂ CH ₂ CH ₃ , more especially CH ₂ C0 ₂ H;

[0681] Q is

[0683] Z is selected from -(CH ₂ ) _p -A-(CH ₂ ) _q -A'-(CH ₂ ) _r -B and -<CH ₂ ) _S -B; especially where

A and A' are independently selected from -0-, -CH ₂ - and -CH=CH- and B is selected from optionally substituted aryl or optionally substituted heterocyclyl, especially unsubstiruted aryl or unsubstituted heterocyclyl, more especially phenyl or pyridyl, most especially phenyl. In particular embodiments, Z is -(CH ₂ ) ₆ phenyl, -(CH ₂ ) ₂ 0(CH ₂ ) ₃ pheny! or -(CH ₂ ) ₂ -CH=CH-(CH ₂ ) ₂ phenyl; and

[0684] Rioo is selected from C ₃ . ₈ cycloalkyl, especially C ₄ . ₇ cycloalkyl, more especially

C ₅ ^cycloalkyl. Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptanyl, and cyclooctanyl, especially cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptanyl, more especially cyclopentyl and cyclohexyl.

[0685] In particular embodiments, the compounds of formula (IB) are selected from compounds of formula ID):

[0687] wherein J is selected from -CH2-, -CH=CH-, -O- and -S-;

[0688] R.200 is selected from hydrogen and Cl-6alkyl;

[0689] R ₃ oo is selected from cycloalkyl;

[0690] R400 is selected from optionally substituted aryl and optionally substituted heterocyclyl; and

- I l l - [0691] u is an integer from 1 to 5, or a pharmaceutically acceptable salt thereof.

[0692] In particular embodiments, the compounds of formula (ID) are selected from:

[0693]

[0694] Compound (i): K = -CH ₂ CH ₂ - and v is 2;

[0695] Compound (ii): K is -CH ₂ -0- and v is 2;

[0696] Compound (iii): is -CHOH- and v is 2; and

[0697] Compound (iv): is -CH ₂ CH ₂ - and v is 1

[0698] or a pharmaceutically acceptable salt thereof.

[0699] The compounds of formula (IB) and (ID) may be synthesized from Boc-protected D-alariine precursors in which the alanine methyl group is modified with a cycloalkyl group, for example, D-cyclohexylalanine and D-cyclopentylalanine using methods known in the art. For example, the carboxyl group of the Boc-protected modified D-alanine may be converted to an aldehyde via a Weinrub amide and then subject to Wittig reaction with a phosphorane such as Ph3P=CH ₂ C0 ₂ CH ₃ to an unsaturated Boc-N-y-amino acid ester. The Boc-protecting group may be removed and the amino group reacted with a suitable arylalkyl carboxylic acid, arylalkenyl carboxylic acid or arylalkylOalkyl carboxylic acid using standard techniques for amide bond formation. The double bond of the unsaturated γ-amino acid portion may then be reduced by hydrogenation, for example, with H ₂ and Pd C and finally the ester group may be hydrolyzed, for example, with base to provide the free carboxylic acid. If the carboxylic acid used to form the amide comprises a double bond, for example, an arylalkenyl carboxylic acid, the reduction of the unsaturated γ-amino acid double bond may be performed before amide formation.

[0700] While these compounds may be presented neat, it is generally preferred that they are formulated in suitable pharmaceutical compositions as described below.

5. Therapeutic and Prophylactic Uses

[0701] In accordance with the present invention, it is proposed that PLA2G2A inhibitors are useful as actives for the treatment or prophylaxis of excess adiposity, including adiposity-related conditions as described above, which include conditions such as obesity and conditions of localized, abnormal increases in adiposity such as, but not limited to, lipoma and lipomatosis, as well as type II diabetes, metabolic dysfunction, cardiovascular diseases and more generally, metabolic syndrome. Such inhibitors can be administered to a patient either by themselves, or in pharmaceutical compositions where they are mixed with a suitable pharmaceutically acceptable carrier.

[0702] Depending on the specific conditions being treated, the PLA2G2A inhibitors drugs may be formulated and administered systemically or locally. Techniques for formulation and administration may be found in "Remington's Pharmaceutical Sciences," Mack Publishing Co., Easton, Pa., latest edition. Suitable routes may, for example, include oral, rectal, transmucosal, or intestinal administration; parenteral delivery, including intramuscular, subcutaneous, intramedullary injections, as well as intrathecal, direct intraventricular, intravenous, intraperitoneal, intranasal, or intraocular injections. For injection, the drugs of the invention may be formulated in aqueous solutions^ preferably in physiologically compatible buffers such as Hanks' solution, Ringer's solution, or physiological saline buffer. For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.

|0703] The drugs can be formulated readily using pharmaceutically acceptable carriers well known in the art into dosages suitable for oral administration. Such carriers enable the compounds of the invention to be formulated in dosage forms such as tablets, pills, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated. These carriers may be selected from sugars, starches, cellulose and its derivatives, malt, gelatin, talc, calcium sulfate, vegetable oils, synthetic oils, polyols, alginic acid, phosphate buffered solutions, emulsifiers, isotonic saline, and pyrogen-free water.

[0704] Pharmaceutical compositions suitable for use in the present invention include compositions wherein the active ingredients are contained in an effective amount to achieve its intended purpose. The dose of drug administered to a patient should be sufficient to effect a beneficial response in the patient over time such as (1) a reduction in total body mass, (2) reduction in adipose tissue inflammation; (3) reduction in insulin intolerance or resistance, (4) reduction in glucose intolerance, (5) reduction in or inhibition of elevation of macrophage numbers infiltrating into adipose tissue, (6) reduction in PGE ₂ levels in adipose tissue, (7) prevention of cardiovascular abnormalities such as cardiac fibrosis and remodeling in the heart, (8) reduction in PGE ₂ release from adipose immune cells, (9) protection against diet-induced metabolic syndrome, or (10) reduced adiposity. The quantity of the drug(s) to be administered may depend on the subject to be treated inclusive of the age, sex, weight and general health condition thereof. In this regard, precise amounts of the drug(s) for administration will depend on the judgment of the practitioner. In determining the effective amount of the drug to be administered in the modulation of type II diabetes, metabolic dysfunction,

cardiovascular diseases and more generally, metabolic syndrome, the physician may evaluate adipose immune cell or adipose tissue levels of PLA2G2A, adipose immune cell of adipose tissue levels of a PGE ₂ , degree of adiposity (e.g., using skin folds), glucose levels, insulin levels, blood pressure, High Density Lipoprotein (HDL) levels, triglycerides levels, uric acid levels etc. In any event, those of skill in the art may readily determine suitable dosages of the drugs of the invention.

[0705J Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.

[0706) Pharmaceutical preparations for oral use can be obtained by combining the active compounds with solid excipient, optionally grinding a resulting mixture, and processing the mixture of

^■ c

granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as., for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium

carboxymethylcellulose, or polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate. Such compositions may be prepared by any of the methods of pharmacy but all methods include the step of bringing into association one or more drugs as described above with the carrier which constitutes one or more necessary ingredients. In general, the pharmaceutical compositions of the present invention may be manufactured in a manner that is itself known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes.

(0707) Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.

[0708] Pharmaceutical which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push- fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added. [0709] Dosage forms of the drugs of the invention may also include injecting or implanting controlled releasing devices designed specifically for this purpose or other forms of implants modified to act additionally in this fashion. Controlled release of an agent of the invention may be effected by coating the same, for example, with hydrophobic polymers including acrylic resins, waxes, higher aliphatic alcohols, polylactic and polyglycolic acids and certain cellulose derivatives such as hydroxypropylmethyl cellulose. In addition, controlled release may be effected by using other polymer matrices, liposomes or microspheres.

[0710] The drugs of the invention may be provided as salts with pharmaceutically compatible counterions. Pharmaceutically compatible salts may be formed with many acids, including but not limited to hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, etc. Salts tend to be more soluble in aqueous or other protonic solvents that are the corresponding^free base forms.

[0711] For any compound used in the method of the invention, the therapeutically effective dose can be estimated initially from cell culture assays. For example, a dose can be formulated in animal models to achieve a circulating concentration range that includes the IC50 as determined in cell culture (e.g., the concentration of a test agent, which achieves a half-maximal inhibition of a PLA2G2A. Such information can be used to more accurately determine useful doses in humans.

[0712] Toxicity and therapeutic efficacy of such drugs can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD50/ED50. Compounds that exhibit large therapeutic indices are preferred. The data obtained from these cell culture assays and animal studies can be used in formulating a range of dosage for use in human. The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50 with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. The exact formulation, route of administration and dosage can be chosen by the individual physician in view of the patient's condition. (See for example Fingl et al, 1975, in "The Pharmacological Basis of Therapeutics", Ch. 1 pi).

[0713] Dosage amount and interval may be adjusted individually to provide plasma levels of the active agent which are sufficient to maintain PLA2G2A inhibition. Usual patient dosages for systemic administration range from 1-2000 mg/day, commonly from 1-250 mg/day, and typically from 10-150 mg/day. Stated in terms of patient body weight, usual dosages range from 0.02-25 mg/kg/day, commonly from 0.02-3 mg/kg/day, typically from 0.2-1.5 mg/kg/day. Stated in terms of patient body surface areas, usual dosages range from 0.5-1200 mg/m ² /day, commonly from 0.5-150 mg/m ² /day, typically from 5-100 mg/m ² /day. [0714] Alternately, one may administer the compound in a local rather than systemic manner, for example, via injection of the compound directly into a tissue, which is suitably subcutaneous or omental tissue, often in a depot or sustained release formulation.

[0715] Furthermore, one may administer the drug in a targeted drug delivery system, for example, in a liposome coated with tissue-specific antibody. The liposomes will be targeted to and taken up selectively by the tissue.

[0716] In cases of local administration or selective uptake, the effective local concentration of the agent may not be related to plasma concentration.

[0717] In order that the invention may be readily understood and put into practical effect, particular embodiments will now be described by way of the following non-limiting examples.

EXAMPLES

EXAMPLE 1

PLA2G2A BUT NOT PLA2G16 OR OTHER PLA2 PROTEINS EXAMINED IS UP-REGULATED IN RAT

ADIPOSE TISSUE BY HCHF FEEDING

10718] The inventors' first objective was to investigate which PLA2 isozymes, if any, promote adiposity and metabolic dysfunction. Increased PLA2 expression in adipose tissue might potentially dampen lipolysis through PGE ₂ -EP ₃ -Goi-cAMP signaling, thereby promoting adipocyte and metabolic dysfunction together with the cardiovascular symptoms of metabolic syndrome (Jaworski et al, 2009a). Rats were fed a HCHF diet in order to induce adiposity and the symptoms of metabolic syndrome (Panchal et al, 201 1). Relative to rats fed a diet containing CS, those receiving the HCHF diet for 16 weeks became obese, gaining 54+4% body weight from week 0 to 16 and 1 12+17% total visceral fat compared to control CS rats (20). The mRNA expression in adipose tissue of a series of PLA2 isozymes currently recognized for their roles in inflammation (pla2g2a, pla2g4a, pla2g5, pla2g7 and pla2gl0) or lipid metabolism (pla2g6 and pla2gl6) was measured. The expression of pla2g2a, pla2g6, pla2g4a, pla2g7 and pla2gl0 genes was extremely low in CS-fed normal rats but significantly elevated in HCHF-fed obese rats. Although pla2g6, pla2g4a and pla2g7 were up- regulated in response to HCHF feeding, their relative expression levels were much lower than for pla2g2a, which was elevated— 20 fold (Figure 1 A). Correspondingly, pla2g2a protein expression was substantially increased in adipose tissue from HCHF-fed obese rats compared to CS-fed normal rats (Figure IB). The plasma and whole adipose tissue PGE2 concentrations were elevated by HCHF compared to CS feeding, correlating with increased adiposity (Figure 1C,D). The inventors compared pla2gl6 mRNA expression in rat adipose tissue, given that it is reportedly a regulator of adipocyte function and lipid metabolism in mice and over-expressed in ob/ob mice adipose tissue. Pla2gl6 was expressed in rat adipose tissue.Jbut expression was unchanged by HCHF feeding (Figure 1 A). Of interest, in a much longer study, the inventors observed that pla2g!6 gene expression was unchanged in adipose tissue from rats and mice (Figure 7) following chronic (16 weeks) HCHF feeding. This finding appears to be at odds with those reported elsewhere for pla2gl6 in acute fed/fasted mice (Jaworski e/ a/., 2009b).

EXAMPLE 2

KH064 ATTENUATES ADIPOSITY IN DIET-INDUCED OBESE RATS

[0719] H064 is an orally active, potent and isoform-selective inhibitor of the enzyme PLA2G2A and a crystal structure for the inhibitor in comple with this enzyme has been previously reported (Hansford et al, 2003). The increased adiposity exhibited by rats fed a HCHF diet for 16 weeks (Figure 2) was attenuated by oral administration of H064 (5mg/kg day) between weeks 8-16, with marked prevention of total visceral fat deposition (+ H064, Figure 2C-D) and body weight gain (weeks 8- 16 HCHF, 19+ 1 %; +KH064, 9+ 1 %; Figure 2A.B). Treatment with KH064 also selectively attenuated retroperitoneal and omental fat rather than epididymal fat deposition (Figure 2D). Besides improvements in adiposity, KH064 treatment from weeks 8-16 also attenuated the increases in plasma and whole adipose tissue PGE ₂ concentrations seen in HCHF rats (Figure 3A,B). Adipose tissue immunohistochemistry demonstrated that treatment with KH064 also prevented the significant increase in crown formation and macrophage infiltration as determined by EDI staining (Figure 7). Treatment with H064 also prevented the increase in heterogeneity of adipocyte size observed following 16 weeks of HCHF feeding (Figure 7). Table 2 shows several cardiovascular parameters, which were ameliorated in HCHF fed rats in response to H064 administration.

TABLE 2

IN VIVO RESPONSES OF KH064 ON THE REGULATION OF CARDIOVASCULAR PARAMETERS THAT

WERE SIGNIFICANTLY ELEVATED IN RATS ON HCHF VERSUS CS DIETS.

Parameter CS HCHF HCHF + KH064

(16 weeks) (16 weeks) (16 weeks)

Heart rate (bpm) 249±9 251±21 244±10

(n=6) (n=6) (n=6) rVSd (mm) 1.67±0.09 1.86±0.06* 1.71±0.07**

(n=6) (n=6) (n=6)

LVIDd (mm) 6.73±0.24 7.57±0.24* 6.80±0.15**

(n=6) (n=6) (n=6)

LVPWd (mm) 1.69±0.1 1.95±0.1 * 1.65±0.04**

(n=6) (n=6) (n=6) rVSs (mm) 2.78±0.15 2.73±0.09 3.28±0.13*

(n=6) (n=6) (n=6)

LVIDs (mm) 3.93±0.39 4.9l±0.23* 3.83±0.14**

(n=6) (n=6) (n=6)

LVPWs (mm) 2.58±0.17 2.64±0.14 3.12±0.10*

(ii=6) (n=6) (n=6)

E/A ratio 1.6±0.1 1.29±0.1 * 1.53±0.02**

[0720] bpm - beats per minute; mm - millimeter; IVS --interventricular septum; LVID - left ventricular internal diameter; LVPW - left ventricular posterior wall thickness; d - diastole; s - systole; E - early wave; A - atrial wave.

EXAMPLE 3

PLA2G2A OVEREXPRESSION AND INHIBITOR ACTION IN IMMUNE CELLS NOT ADIPOCYTES

[0721] Separation of whole adipose tissue into adipocyte and SVC fractions confirmed that pla2g2a was mainly expressed in the SVC fraction rather than the adipocytes of normal adipose - tissue. Furthermore, HCHF feeding induced over-expression of pla2g2a but only in the SVC (Figure 3C). In contrast, pla2gl 6 was predominantly expressed in the adipocyte fraction from whole adipose tissue (Figure 8) and its expression levels were not affected by HCHF feeding (as shown in Figure 1A).

' [0722] The pla2g2a secretory enzyme is regarded as an important generator of inflammatory lipid mediators during immune cell activation, including PGE ₂ produced by cyclooxygenase (Reddy and Herschman, 1996; Scott et al, 1991; Wery et al, 1991 ). The inventors focused on PGE ₂ as it has been implicated as a major paracrine anti-lipolytic factor in adipocytes (Jaworski et al, 2009b; Mater et al, 1999). The inventors found that PGE ₂ inhibited cAMP production in 3T3-L1 adipocytes and further established the involvement of EP3 receptor and pertussis toxin- sensitive Gai-proteins in this process (Figure 9). In line with the above in vitro results, reduction of lipolysis in the presence of PGE ₂ was observed in rat whole adipose tissue explants (Figure 9). To establish that pla2g2a was primarily expressed in the SVC enriched with immune cells and that this was where KH064 was acting, the SVC were pre-treated with H064 prior to LPS stimulation. As expected, LPS stimulated the production of PGE ₂ in the SVC and KH064 prevented this increase in PGE ₂ production (Figure 3D). Further, KH064 at a relatively high concentration (1 mM) showed no inhibition of any PLA2 enzymatic activity in adipose tissue from CS-fed rats. These results clearly trace the pharmacological responses of H064 on pla2g2a to the immune cell-rich SVC in whole adipose tissue and not the adipocyte fraction.

EXAMPLE 4

REGULATION OF LIPOLYSIS VIA PLA2G2A AND PGE ₂ IN IMMUNE CELLS

[0723] Many different types of resident and infiltrated immune cells, such as

macrophages, monocytes, T-cells and mast cells, contribute to development of adipocyte dysfunction (Feuerer et al, 2009; Liu et al, 2009; Nishimura et al, 2009). However, their individual roles and specific importance in regulating lipid homeostasis and adipocyte function in diet-induced obesity are not yet clear. In the present study, the inventors investigated whether some or all of these cells regulate lipolysis via pla2g2a/PGE ₂ in adipose tissue. Since they were not able to isolate infiltrated rat adipose tissue immune cells in sufficient quantity or purity for in vitro studies, they chose five primary or cultured human cell types that are closely associated with adiposity and metabolic dysfunction. The five immune cell types, human monocyte derived macrophages (HMDM), peripheral blood mononuclear cells (PBMC), HMC- 1 , Jurkat and TOP- 1 , all showed increased PGE ₂ production following stimulation with palmitic acid, the most common and abundant nutritional fatty acid in the Western-style diet that plays a major role in inducing adipocyte and metabolic dysfunction in obese subjects (Guilherme et al. , 2008). Treatment of each cell type with KH064 markedly reduced (2-5 fold) this increased PGE ₂ production (Figure 4). To support the notion that KH064 was inhibiting palmitic acid-induced PGE ₂ production via the pla2g2a en2yme in these cell types, LPS was separately used to elicit PGE ₂ production in the above five immune cell types (Figure 10). Of the five immune cell types, HMDM, PBMC and HMC-1 showed increased PGE ₂ production following LPS stimulation, and KH064 treatment markedly reduced the increased PGE ₂ production in these cells (Figure 10). However, Jurkat and THP-1 did not show a significant increase in PGE ₂ production after stimulation with LPS, suggesting that these cell types were not involved in LPS-induced production of PGE ₂ . These results suggest that, in addition to macrophages (Kosteli et al, 2010), other immune cell types such as monocytes, T-cells and mast cells may also secrete anti-lipolytic factors such as PGE ₂ to reduce lipolysis and free fatty acid concentrations, thereby promoting adiposity.

EXAMPLE 5

PLA2G2A AND PGE ₂ INHIBITION RESTORES LIPOLYSIS IN VIVO

[0724] One approach to improving adipocyte function is to decrease fat stores in adipose tissue by stimulating lipolysis and oxidation of released fatty acids (Langin, 2006). Since the pla2g2a inhibitor H064 restored lipolysis and attenuated adiposity, the present inventors investigated whether inhibiting PGE ₂ in vivo would stimulate enhanced release of fat from adipose towards better fat utilization and oxidation in the liver and skeletal muscle. As expected, plasma non-esterified fatty acids were increased with H064 treatment compared to untreated HCHF animals at week 16, suggesting an increase in lipolysis from adipose tissue stores (Figure 5C). During lipolysis, either through acute weight loss or metabolic disease, macrophages and other immune cells may play important roles as transporters of lipids from the adipose to liver for metabolism either as bile acids or increased fatty acid oxidation for energy production, possibly involving the reverse cholesterol transport pathway (Kosteli et al., 2010; Red Eagle and Chawla, 2010). HCHF rats showed increased total lipid content and steatosis in the liver at 16 weeks compared to CS-fed rats (Figure 5D; Figure 1 1 ). Plasma liver enzymes, AST and ALT concentrations were elevated in HCHF-fed rats compared to CS-fed rats suggesting mild liver dysfunction (Figure 5E). Treatment with KH064 from week 8-16 attenuated this increase in liver enzymes and thereby improved liver function (Figure 5E). Further, the increased total lipid content in the liver was not attenuated with KH064 treatment from weeks 8-16 (Figure 5D). Histological analysis showed that livers from KH064-treated rats had accumulation of fat droplets, with decreased functional damage to liver accompanying attenuation of increased liver and stress enzymes (Figure 1 1; Figure 5C, E). Increased plasma concentrations of ALP (Figure 5E) after treatment with KH064 suggest that these rats may either have increased excretion of cholesterol through the bile, or decreased absorption of fat from the intestines. Extractable fecal lipid content was increased with KH064 treatment (Fig. 5F). Furthermore, genes involved in lipid metabolism and energy expenditure in the liver, such as peroxisome proliferator-activator receptor-a (Ppara), sterol regulatory element binding transcription factor 1 (Srebfl), uncoupling protein 2 (Ucp2), peroxisome proliferator-activator receptor-γ (Pparg) and hepatic lipase (Lipc), were suppressed in the HCHF rats but restored in the HCHF rats treated with H064 (Figure 5B). Similarly in skeletal muscle, carnitine palmitoyltransferase 1 (Cptl) and Ucp3 genes involved in energy expenditure were suppressed in the HCHF rats and restored in the HCHF rats treated with KH064 (Figure 5B). Other genes that are involved in lipid and glucose metabolism, including Pparg, Ppargcl a and pyruvate dehydrogenase kinase 4 (Pdk4) in adipose, liver and skeletal muscle, were up-regulated in KH064 -treated rats compared to HCHF-fed rats (Figure 5B, G, H). Together with the altered expression of lipid-handling genes in the adipose, liver and skeletal muscle, these results suggest that restoring lipolysis with H064 may induce better fat utilization, excretion and expenditure to protect against adiposity.

EXAMPLE 6

PLA2G2A PROMOTES LIPOLYSIS AND PROTECTS AGAINST DIET-INDUCED METABOLIC

SYNDROME

[0725] Attenuation of adipocyte dysfunction or adiposity improved the metabolic and cardiovascular symptoms of metabolic syndrome in animal models and clinical studies (Iyer et al, 2010; Van Gaal et al, 2006). In the current study, alterations in metabolic parameters in HCHF treated compared to CS treated rats included impaired glucose and insulin tolerance (Figures 6C-E), increased plasma insulin concentrations (Figure 6B), increased systolic blood pressure (Figure 12), and abnormalities in cardiac structure and function (Figures 6F-H). Most of these parameters were attenuated by treatment with KH064 (Figure 6F-H; Figure 12), including the excessive collagen deposition in the left ventricle of the heart in HCHF rats.

DISCUSSION OF EXAMPLES 1-6

[0726] The results disclosed herein present important new evidence for involvement of the secretory phospholipase A2 enzyme, pla2g2a, in diet-induced adiposity and metabolic and cardiovascular dysfunction. PLA2 enzymes are important in the pathogenesis of chronic inflammatory diseases and are thought to be important in lipid metabolism. Here the present inventors show that the specific isozyme pla2g2a is an important mediator in the crosstalk between immune and metabolic systems in adipose tissue relevant to lipid and energy homeostasis, metabolic and cardiovascular function. In rats given a diet rich in saturated fats and carbohydrates, pla2g2a was upregulated in the SVC fraction, but not the adipocyte fraction, of adipose tissue. The present inventors found that a selective inhibitor of pla2g2a (K.H064) (Hansford et al, 2003), administered systemically by oral gavage to HCHF-fed rats, inhibited the development of obesity, adiposity, insulin resistance and glucose intolerance. The pla2g2a inhibitor also attenuated changes in expression of genes involved in energy expenditure and fatty acid oxidation in the adipose, liver and skeletal muscle, and other features of metabolic and cardiovascular dysfunction normally induced by nutritional overload.

[0727] These in vivo effects of KH064 were linked to preventing PGE ₂ release in adipose tissue from immune cells and not adipocytes. Immune cells infiltrate adipose tissue during obesity and metabolize fatty acids. The inventors propose that these immune cells over-express pla2g2a which in turn generates metabolites of phospholipids such as PGE2 to act on secondary target cells, adipocytes, to inhibit lipolysis through a PGE2- EP3-cAMP pathway. They have also shown that an inhibitor of pla2g2a inhibits in vitro palmitate- or LPS-stimulated release of PGE2 from immune cells such as macrophages, T-cells, monocytes and mast cells that infiltrate or are resident in adipose tissue in obese humans. In vivo, this inhibitor decreased plasma and adipose PGE2 concentrations, restored and stimulated lipolysis in adipose tissue, and protected against adiposity in diet-induced obese rats. This suggests a novel role for these immune cells in regulating lipolysis through EP3-Gai-cAMP signaling during diet-induced obesity. PGE ₂ regulates adipocyte dysfunction and contributes to the anti-lipolytic pathways via EP3 receptors thereby decreasing cA P concentrations (Jaworski et al, 2009a).

However, this is the first study to show that modulating PGE2 secretion through inhibition of pla2g2a from key immune cells resident and infiltrated into adipose tissue reverses diet-induced adiposity and the symptoms of metabolic syndrome.

[0728] In summary, the results presented herein demonstrate that, of the different PLA2 enzymes expressed in adipose tissue of obese rats, pla2g2a is by far the most up-regulated both at mRNA and protein levels in response to diet-induced obesity. This enzyme is localized to immune cells in adipose tissue, rather than adipocytes. Inhibition of pla2g2a in immune cells may decrease fat stores by preventing PGE2 biosynthesis to stimulate lipolysis and oxidation of the released fatty acids. Importantly, a potent and specific inhibitor of human pla2g2a prevented diet-induced adiposity, insulin resistance, metabolic dysfunction and cardiovascular disease in rats. These results indicate that modulation of adipose tissue homeostasis by preventing the endocrine and paracrine stimulus from immune cells rather than a direct action of adipocytes themselves may be a novel approach to reverse diet-induced metabolic syndrome in humans.

MATERIAL AND METHODS

ANIMALS AND DIETS

[0729] Male Wistar rats were bred at the University of Queensland Biological Resources facility. AH experimental protocols were approved by the Animal Experimentation Ethics Committee of The University of Queensland, under the guidelines of the National Health and Medical Research Council of Australia. Rats were given ad libitum access to food and water and were housed in 12 h light/dark conditions. The corn starch (CS) and high carbohydrate high fat (HCHF) diets have been previously described (Panchal et ai, 201 1). H064 (5 mg/kg/day suspended in olive oil) was administered daily by oral gavage to HCHF rats, starting at week 8 of the study protocol. Control HCHF-fed rats received equal amounts of olive oil as oral gavage vehicle. Body weight, food and water intakes of both groups were measured daily.

ADIPOCYTES AND STROMAL VASCULAR CELLS ISOLATION

[0730] Rat adipose tissue was minced and digested in DMEM supplemented with 1 OOmM HEPES, 1.5% BSA and 0.6 mg mL collagenase B (Roche Applied Science, Penzberg, Germany) at 37°C for 45 min. Floating adipocyte fraction was isolated by centrifugation at 100 g for 10 min and the SVC was obtained by subsequent centrifugation at 1000 g for 10 min.

GENE EXPRESSION

[0731] Tissue samples were homogenized in Qiazol lysis reagent (Qiagen). R A was extracted from the homogenate according to the RNeasy mini kit (Qiagen) manufacturer's instructions and concentration determined by measuring absorbance at 1=1260/280 nm on a spectrophotometer. Total RNA was then reverse transcribed with Superscript III (Invitrogen) using random oligo dT primer. RT-PCR was run on ABI PRISM 7500 (Applied Biosystems, Australia) with cycle conditions as previously described (Suen et al, 2010) and target gene was normalized to 18S rRNA. Primer sequence is shown in Table 3.

TABLE 3

PRIMER SEQUENCES FOR TARGETED GENES

Name Forward primer Reverse primer

Rat primers

Adipoq GAGAAGGGAGACGCAGGTGTTCT TGCCAGGGGTTCCGGGAAAG

Atgl CCCGGTTGTCCCCCAGGAAGA TCCAGCAGGGCCTCGTTGAGT

Glut2 ACGGCTGTCTCTGTGCTGCTTG ACACCAGTCCCAGCGACATGAAGA

Hsl GGCGCCTCCTCATGGCTCAA GTGGGGCGCAGTGTCTCTGT

Hexokinase TCGCCGCAGCAGGATGATCG GGTCAACCTTCTGCACTTGGTTTTG mGDPH AGTGGCATTCGCCCGCTTGT GAGGCCACTGTCGCTGACTTCC

Ppara AGGCCCTGCCTTCCCTGTGAA GGGCCACAGAGCACCAATCTGTG Pparg ACCCAGAGCATGGTGCCTTCG TGGTGGGCCAGAATGGCATCTCT

Ppargcla ACTGGCGTCATTCAGGAGCTGGA CCAACCAGGGCAGCACACTCT

Pdk4 CCAGGCCAACCAATCCACATCGT CCGTGGCCCTCATGGCATTCTTG

Lep AGCAGGCTGCAGGGCTCTCT GGGAGCCCGGTGGTCTTGGA

Cptl TGTGGCCGACCACGGATACG GCGCAGGGCGTTCGTTTCTGA

Ucp2 GGGCTCAGAGCATGCAGGCATC TGGGCCTGGAAGCGGACCTTT

Lipc GGTACAGCCTGGGAGCACACG CTGCAGGGTCCAGCCCTGTGA

Pla2g2a GCCTTTGGCTCAATTCAGGTCCA ACCCACACCACAATGGCAACC

Pla2g4a ACGGTTCAGCATGGCACTGT CCACCACAGGCACATCACGT

PIa2g5 GTGCTGTCGGATGCACGACC AGGAGTCGTGTTCGCAGATGACT

Pla2g6 TCATCAGCTGCGCCAACAGC TCTGGGCGTGGCAGTACTGT

Pla2g7 CACGGTCTCGGAGCCTTCAGGA TGCGG ATGC AG ATCCGTCTCTATGT

Pla2gl0 CAGCGAAGCAACCAGGAGGTCAC CGGCGATCGAGGACCAACACA

Pla2gl6 CATCCACGGCGCTGCTAAGCT TCCAGGCTTGGGTTCTGGTATGG

Srebn GGACTGGGCTGTACACGGTGC CTGGGCTGGGCTGAGCGATA

18s CGGCCGGTACAGTGAAACTG GCGCCCGTCGGCATGTATTA

Mouse

primers

Pla2gl6 TACAGGCTGACCAGCGAGAACT CCACTCCAGCGATGCCTACCG

IMMUNOBLOT

10732] Adipose tissue was homogenized in 50 mM Tris (pH 7.4), 1% SDS and protease inhibitor cocktail (Roche Applied Science). Protein concentration was determined using Nanodrop ND-100 v3.2.1 Protein A280 (Bioscience, Australia). Equal amounts of proteins were loaded and separated on denaturing SDS-PAGE, and transferred onto polyvinylidene fluoride membrane. Protein levels of pla2g2a were detected using polyclonal pla2g2a antibody (Abeam) and loading control was determined using polyclonal anti-GADPH (Sigma-Aldrich). Relative densitometry analysis on protein bands was performed using ImageJ 1.40e software.

CELL CULTURE

[0733] HMC-1 cells were cultured in IMDM supplemented with 10% fetal calf serum (FBS), 10 U/mL penicillin, 10 U/mL streptomycin, 2 mM L-glutamine (Invitrogen) and 20 1 1 M 2- mercepethanol. Jurkat E6.1 and THP-1 cells were cultured in RPMI supplemented with 10% FBS, 10 U/mL penicillin, 10 U/mL streptomycin, 2 mM L-glutamine, 2 mM NEAA and 1 mM HEPES. Human peripheral blood mononuclear cells (PBMC) and monocyte-derived macrophages (HMDM) were cultured in IMDM with 10% FBS, 10 U/mL penicillin, 10 U/mL streptomycin and 2 mM L-glutamine. HMDM was supplemented with 104 U/mL recombinant human macrophage colony stimulating factor (PeptroTech Inc, Rocky Hill, New Jersey, USA) for differentiation.

PBMC AND HMDM ISOLATION

[0734] PBMC and HMDM cells were harvested from buffy coat of anonymous human donors (Australian Red Cross Blood Service, Brisbane). PBMC were isolated and purified using Ficoll-Paque PLUS (GE Healthcare Bio-Science, Uppsala) density centrifugation and repeated washings with ice-cold water to remove contaminating erythrocytes. For HMDM, CD 14+ monocytes were positively selected using CD 14+ MACS magnetic beads (Miltenyi Biotech, Auburn, CA) after successive magnetic sorting and washings. CD14+ monocytes were then plated at a density of 1.5 x 106 cells/mL and supplemented with 104 U/mL of macrophage-colony stimulating factor (M-CSF). Cells were then supplemented after 5 days with fresh medium containing with 102 U/mL M-CSF. Cells were harvested by gentle scraping in saline solution on day 7.

ELISA

[0735] Cells were seeded at a density of 1 x 106 cells mL and allowed to adhere overnight. On the day of experiment, cells were pre-treated with H064 (10 pM) for 15 min at room temperature prior to stimulation with LPS (1 pg/mL) or palmitic acid (0.5 mM). After 6 h incubation at 37° C, culture supernatants were collected and PGE ₂ levels were measured using monoclonal PGE2 EIA kit. Blood samples were collected from the abdominal aorta after euthanasia, serum PGE ₂ and insulin concentrations were determined using a PGE2 metabolite and rat insulin kit respectively

PHYSIOLOGICAL PARAMETERS

[0736] Oral glucose tolerance and clearance test were previously described (Panchal et al. ,

201 1 ). Plasma lipids and enzyme concentrations were measured by the Veterinary Pathology Service of The University of Queensland, Australia (Panchal et al, 201 1). Systolic blood pressure of rats was measured as previously described (Panchal et al , 201 1 ). ECHOCARDIOGRAPHY STUDIES AND HEART PREPARATION

[0737] Echocardiographic examination was performed in all rats after 16 weeks as previously described (Iyer et al., 2010). Evaluation of the left ventricular function of all the rats in all treatment groups after 16 weeks was performed as previously described (Iyer et al. , 2010).

HlSTOPATHOLOGICAL ANALYSIS

[0738] Collagen analysis was performed in excised hearts using picrosirius red staining as previously described (22). Excised liver and retroperitoneal adipose tissue were fixed with 10% neutral buffered formalin for 1 day. Thin sections (7 urn) of the liver were stained with Milligan's trichrome stain to determine structural changes as previously described (22). Thicker sections (10 gm) were fixed in 4% PFA for 15 min, cleared in xylene, then rehydrated in ethanol PBS before microwave antigen retrieval in buffer (10 mM Citrate, 2mM EDTA, 0.5% Tween 20 pH6.2). After washing, endogenous peroxidase activity was neutralized by incubation in buffer (30% H202/TBS) for 10 min. Washed sections were blocked (1% BSA 1% goat serum/TBS) for 20 min prior to incubation along with anti-rat EDI antibody 1 : 150 for 2h. Sections were washed, incubated in MACH4 probe for 10 min, washed, incubated in MACH4 HRP polymer (Biocare Medical) for 10 min, washed then incubated in DAB (Sigma) for 10 s. Reactions were stopped with water; sections were dehydrated with ethanol and cleared in xylene before mounting with Safety Mount No. 4.

TOTAL LIPID CONTENT

[0739] The extraction of tissue and fecal lipids was undertaken by manual solvent extraction as previously described (23) in all rats after 16 weeks using a 2: 1 chloroform/methanol mixture with 0.1% butylated hydroxytoluene as an anti-oxidant.

DRUG

[0740] The inhibitor, 5-(4-benzyloxyphenyl)-45-(phenyl-heptanoylamino)-pentanoic acid (KH064), of phospholipase A2 (pla2g2a) was synthesized, purified and enzymatically characterized as we have previously described (compound 2b in (Hansford et al, 23)).

STATISTICAL ANALYSIS

[0741] Data were plotted and analyzed using GraphPad Prism version 5.00 for Windows (GraphPad Software, San Diego, CA). Statistically differences in pairwise comparisons between treatments were assessed using Student's t-test and changes in body weight were assessed by two-way ANOVA. Significance was set at *P <0.05, **P <0.01 and ***P <0.001. ΑΠ values of independent parameters are shown as mean ± SEM of least three independent experiments (n > 3) unless otherwise stated. 3T3-L1 DIFFERENTIATION

[0742] 3T3-L1 fibroblasts were maintained in DMEM supplemented with 10% FBS, 10 U/mL penicillin, 10 U/mL streptomycin and 10 mM glutamine. Differentiation was induced 2 days post confluence in DMEM/10% FBS supplemented with 1.7 p,M insulin, 0.5 mM 3-isobutyl-l- methylxanthine and 2 pM dexamethasone. After 4 days, the differentiating medium was replaced with post-differential medium consisting of DMEM 10%FBS with 1.7 p,M insulin. Fully differentiated 3T3-L1 adipocytes (at least 90% of which showed phenotypic appearance by accumulation of multiple lipid droplets) were then re-fed every 2 days with DMEM/10%FBS.

CAMP ANALYSIS

[0743] 3'-5'-cyclic adenosine monophosphate (cAMP) concentrations were determined using cAMP-GloTm assay (Promega) according to manufacturer's instructions. Compounds were added at specified concentrations and incubated at room temperature for 10 mini For pertussis toxin (PTX)-sensitive experiments, cells were incubated with PTX (300 ng/mL) for 12 h.

DIET-INDUCED OBESE MICE

[0744] C57BL/6 mice were fed with high-fat diet for 16 weeks to induce diet-induced obesity as previously described in (Raddatz et al. 201 1 ).

EXAMPLE 7

SELECTIVITY OF KH064

[0745] The present inventors previously reported the crystal structure of inhibitor H064 bound in the active site of human pla2g2a enzyme (Hansford et al, 2003), along with its dose- dependent inhibitory potency (IC50 0.029 μΜ). This enzyme has a different active site from most other sPLA2 enzymes, while it is similar to human macrophage pla2g5 enzyme against which KH064 is 100 times less potent (IC50 2 μΜ; Levick et al, 2006). KH064 does not bind to or inhibit cPLA2 or iPLA2 enzymes.

EXAMPLE 8

PHARMACOKINETICS OF KH064

[0746] At 5 mg/kg oral dose used in the present study, H064 was detectable in plasma within 15 min and plasma concentrations were relatively constant for 6 h. C _max -0,18-0.2 μg/mL. T _max ~2h. Oral bioavailability. AUC ρ.ο,/AUC i.v. ~4%, however this does not take into account extensive partitioning of the compound to tissues and thus is a substantial underestimate of true oral bioavailability. In fact, after 18-24 h of oral dosing, KH064 was still -0.05 μg/mL in plasma supporting partitioning to tissues. EXAMPLE 9

OFF TARGET EFFECTS OF KH064

[0747] No substantive off target effects have been found for H064. In preclinical work in mice at 300 mg/kg/p.o., it showed no adverse toxic effects. In this work, the present inventors administered H064 (5 mg/kg/day/p.o.) daily from week 8 to 16 to control rats (cornstarch fed). This treatment did not change body weight or significantly affect biochemical markers in plasma (Figure 13). No substantive off-target effects were found for H064 on around 30 human GPCRs, 25 enzymes, and P450 metabolism in liver microsomes and individual P450 enzymes. The inventors also find no activation of whole monocyte-derived human macrophages by 100 μΜ KH064 in a label-free assay (Roche xCelligence) that measures changes of cellular impedance in response to external stimulus - this is a holistic assay of whole cell responses to a drug. They also found that KH064 does not inhibit adipocyte PLA2 (adpla pla2gl 6) in adipose tissue.

EXAMPLE 10

EFFICACY OF KH064 IN RATS

[0748] In previous studies, the present inventors monitored the efficacy of KH064 on carrageenan-induced rat paw swelling and adjuvant-induced rat arthritis. H064 treatment at 5 mg/kg day/p.o. on days 10-13 reduced paw swelling by >95% on Day 14 (Hansford et al, 2003). The expression of pla2g2a correlated with paw swelling, consistent with pla2g2a having a pathogenic role and with effective inhibition of paw oedema by KH064 at 5 mg/kg/day in these rats. Efficacy of KH064 has also been examined in a dozen different disease models in rats (including collagen- induced, adjuvant-induced and monoarticular antigen-induced arthritis; ischemia-reperfusion injury in kidney, liver, heart and intestine; TNBS-induced inflammatory bowel disease, uveitis, uterine contractions, etc) where pla2g2a may play pathological roles, and KH064 was effective at

5 mg/day/p.o. in treating those conditions without evident toxicities.

[0749] Based on the above results, the present inventors treated lean cornstarch fed rats

(control rats in the current study) with KH064 daily from weeks 8-16 without major increase in ALP, ALT, AST, LDH concentrations compared to control cornstarch rats (Figure 13B) suggesting no "toxic" responses from KH064 treatment for 8 weeks (Figure 13 A).

(0750] The present inventors have also shown that there is no change in total lipid content in the liver between HCHF and HCHF+ H064 treatment. FAME GS-MS analysis of the total lipids present in the liver was also performed with and without KH064 treatment. Results from this analysis suggest that at 16 weeks the n-6 pro-inflammatory fatty acids and trans fat decrease with increases in saturated and monounsaturated fatty acids in KH064 treated rats (Table 4). There is also a substantial increase in long chain n-3 fatty acid (C22:6 n3) in the liver. These results suggest that H064 may normalize the pro and anti-inflammatory fatty acids resulting in a homeostatic balance between these otherwise biochemically important lipids.

TABLE 4

LIPID FATTY ACID CONTENT OF KH06 TREATED AND UNTREATED RATS

(n=5 for all groups; g/lOOg total fatty acid content)

EXAMPLE 1 1

SYNTHESIS OF COMPOUNDS (I) TO (rv)

[0751] Compounds (i) to (iv) were synthesized using the following general method:

- 128 - i

(0

[0753 J The amino acid was treated with (a) N(CH ₃ )OCH ₃ in the presence of BOP and DIPEA in DMF thereby forming a Weinreb amide. The Weinreb amide was then reduced with (b) lithium aluminium hydride (LiAIH ₄ ) in THF to produce a Boc-protected aldehyde. The aldehyde was then subject to treatment with a phosporane (c) in THF to produce an unsaturated γ- amino acid ester. The Boc-protecting group was then removed with (d) 1 : 1 Trifluoroacetic acid (TFA) / dichloromethane (DCM) and the deprotected amino group reacted with a (e) suitable carboxylic acid in the presence of BOP and DIPEA in DMF to form an amide bond. The unsaturation on the γ-amino acid portion of the molecule was then reduced by hydrogenation with (f) H ₂ and Pd/C and the ester group removed using (g) sodium hydroxide in THF, MeOH and H ₂ 0.

(S)-5-Cvclohexyl-4-(7-phenylheptanamido)pentanoic acid Compound (i), SB86)

[0754] Ή MR (400 MHz, CDC1 ₃ ) δ 10.77 (1H, br s, OH), 7.28-7.24 (2H, m, ArH), 7.17- 7.14 (3H, m, ArH), 5.80 (lH, br d, J= 9.2 Hz, NH), 4.05 (1H, m, aCH), 2.59 (2H, t, J= 7.8 Hz, ArCH ₂ ), 2.36 (2H, t, J= 7.2 Hz, COCH ₂ ), 2.21 -2.14 (2H, m, Y'CH ₂ ), 1.88-0.78 (23H, br m, yCH + 1 lxCH ₂ ). ^I C NMR (100 MHz, CDC1 ₃ ) δ 177.7, 174.4, 142.6, 128.4, 128.2, 125.6, 46.7, 43.1 , 36.6, 35.8, 34.4, 33.7, 32.7, 31.3, 31.0, 30.8, 29.0, 28.9, 26.4, 26.3, 26.1 , 25.8. ESMS: 388 (M+H). HRMS [M+H] ⁺ for C ₂ 4H ₃₈ N03 ⁺ : Calculated 388.2846 Found 388.2857, (^)-5-Cvclohexyl-4-(3-(3- henylpropoxy)propanamido entanoic acid (Compound (it). SB88)

[0755) Ή NMR (400 MHz, CDC1 ₃ ) δ 10.20 (1H, br s, OH), 7.30-7.23 (2H, m, ArH), 7.20- 7.13 (3H, m, ArH), 6.42 (1H, br d, J= 8.8 Hz, NH), 4.06 (1H, m, aCH), 3.70-3.60 (2H, m, OCH ₂ ), 3.46 (2H, t, J= 6.4 Hz, OCH ₂ ), 2.65 (2H, t, J = 7.8 Hz, ArCH ₂ ), 2.47 (2H, t, J = 5.4 Hz, COCH ₂ ), 2.36 (2H, t, J= 7.2 Hz, y*CH ₂ ), 1.93-0.75 (17H, br m, yCH + 8xCH ₂ ). ^I3 C NMR (100 MHz, CDC1 ₃ ) δ 177.3, 172.5, 141.5, 128.4, 128.3, 125.9, 70.5, 66.8, 46.4, 43.2, 36.9, 34.3, 33.7, 32.7, 32.3, 31.1 , 31.0, 30.9, 26.4, 26.3, 26.1. ESMS: 390 (M+H). HRMS [M+Na] ⁺ for C ₂₃ H ₃₅ N0 ₄ Na ⁺ Calculated 412.2458 Found 412.2467.

(S)-5-CYclohexyl-4^7-phenylhe t-4-enaniido) entanoic acid (Compound (iii)

[0756] Characterized and evaluated as a mixture of (£)- and (Z)-isomers. Major species (Z), minor species (£ , ratio 38:21 (determined by Ή NMR integration). Characterization of major species: Ή NMR (600 MHz, DMSO-d ₆ ) δ 7.43 (1H, br d, 7= 9.0 Hz, NH), 7.27-7.22 (2H, m, ArH), 7.20-7.13 (3H, m, ArH), 5.39-5.26 (2H, m, 2xCH=), 3.83-3.74 (1H, m, aCH), 2.59 (2H, t, J= 7.7 Hz, ArCH ₂ ), 2.33-1.99 (8H, br m, 2xCOCH ₂ + 2xCH ₂ ), 1.75-0.69 (15H, br m, yCH + 7xCH ₂ ). ^{, 3} C NMR (150 MHz, DMSO-d«) 6 174.4, 171.0, 141.7, 129.2, 129.1, 128.3, 128.2, 125.7, 44.9, 42.3, 35.4, 35.3, 35.2, 34.0, 33.8, 33.4, 32.1, 30.6, 30.4, 28.7, 28.3, 26.1, 25.9, 25.7, 23.3. Extensive overlap of major species with minor species, discernible signals of the minor species: Ή NMR (600 MHz, DMSO-d ₆ ) δ 7.45 (lH, br d, J= 9.2 Hz, NH), 5.48-5.29 (2H, m, 2xCH=). ^I3 C NMR (150 MHz, DMSO-de) δ 141.6 (ArC), 129.7 (CH=), 129.5 (CH~), 44.9 (aCH). ESMS: 386 (M+H). HRMS [M+H] ⁺ for

Calculated 386.2690 Found 386.2689.

5-Cvclopentyl-4- 7-phenylheptanamido)pentanoic acid (Compound (iv))

[0757] Ή NMR (600 MHz, DMSO-de) 6 7.46 (1H, br d, J= 8.9 Hz, NH), 7.26 (2H, t, J= 7.5 Hz, ArH), 7.19-7.13 (3H, m, ArH), 3.76-3.69 (1H, m, NCH), 2.54 (2H, \, J= 7.7 Hz, ArCH ₂ ), 2.20-2.10 (2H, m, COCH ₂ ), 2.03 (2H, t, J = 7.2 Hz, COCH ₂ ), 1.78-0.95 (21H, br m, CH + 10xCH ₂ ). ¹³ C NMR (150 MHz, DMSO-de) h 174.4, 171.6, 142.3, 128.2x2, 125.6, 46.9, 40.9, 36.6, 35.5, 35.1 , 32.4, 32.1, 31.0, 30.4x2, 28.4x2, 25.3, 24.7, 24.6. ESMS: 374 (M+H). HRMS [M+H] ⁺ for C ₂₃ H ₃₆ N0 ₃ ⁺ Calculated 374.2690 Found 374.2690.

EXAMPLE 12

ASSAY FOR INHIBITION OF HUMAN PLA2G2A

[0758J A mixed micelle colorimetric assay utilizing a microtiter plate reader was used as described by Reynolds, L. J.; Hughes, L.L.; Dennis, E.A. "Analysis of human synovial fluid phospholipase A ₂ on short chain phosphatidylcholine-mixed micelles: Development of a

spectrophotometric assay suitable for a microplate reader" Anal Biochem.1992, 204, 190- 197.

[0759] Reagents were obtained commercially in the sPhospholipase A ₂ Assay Kit, Cayman Chemical Company MI USA. Buffer (25mM Tris HC1 at pH 7.5, 1 mg mL BSA, 0.3 mM Triton X- 100, 100 mM KC1, 10 mM CaCl ₂ ), substrate (diheptanoyl thio-phosphatidyl choline), DTNB (5,5'-dithiobis(2-nitrobenzoic acid)) and a 96 well plate were all provided. Recombinant human PLA2G2A was provided by the Garvan Institute for Medical Research. The enzyme was found to be homogenous by LCMS and a MS reconstruct yielded a molecular weight of 13,905 g/mole as expected. Standard inhibitor solutions were prepared from anhydrous DMSO. All samples were run in triplicate including the blank and control samples. Data was collected on a Molecular Devices Spectramax 250 Microplate Spectrophotometer using Softmax Pro Microplate Analysis Software v2.21. Diphenylheptanoyi Thio-PC is processed by s-PLA ₂ and the free thiol produced is detected with DTNB (Ellman's Reagent). 5-Thio-2-nitrobenzoic acid is detected spectrophotometrically at 414 nM. IC ₅ o's were determined by assaying inhibitors at a range of concentrations. Inhibitor concentration was plotted as a function of the inverse of the initial velocity (Dixon plot) and extrapolation to the X-axis yielded the IC ₅₀ .

[0760] The results are shown in Table 5:

TABLE 5

[0761] Compound [0762] IC50

(nM

[0763] (i) (SB86) [0764] 20

[0765] (ii) (SB88) [0766] 29

[0767] (iii) [0768] 14

[0772] The disclosure of every patent, patent application, and publication cited herein is hereby incorporated herein by reference in its entirety.

[0773] The citation of any reference herein should not be construed as an admission that such reference is available as "Prior Art" to the instant application.

[0774] Throughout the specification the aim has been to describe the preferred embodiments of the invention without limiting the invention to any one embodiment or specific collection of features. Those of skill in the art will therefore appreciate that, in light of the instant disclosure, various modifications and changes can be made in the particular embodiments exemplified without departing from the scope of the present invention. All such modifications and changes are intended to be included within the scope of the appended claims.

BIBLIOGRAPHY

Altschul, S.F., Madden, T.L., Schaffer, A.A., Zhang, J., Zhang, Z., Miller, W., and Lipman, D.J.

(1997). Gapped BLAST and PSI-BLAST: a new generation of protein database search programs. Nucleic Acids Res 25, 3389-3402.

Barbour, S.E., and Dennis, E.A. (1993). Antisense inhibition of group II phospholipase A2 expression blocks the production of prostaglandin E2 by P388D1 cells. The Journal of biological chemistry

268, 21875-21882.

Bridonneau, P., Chang, Y.F., O'Connell, D., Gill, S.C., Snyder, D.W., Johnson, L., Goodson, T., Jr., Herron, D. ., and Parma, D.H. (1998). High-affinity aptamers selectively inhibit human nonpancreatic secretory phospholipase A2 (hnps-PLA2). J Med Chem 41, 778-786.

Carter, P., Presta, L., Gorman, CM., Ridgway, J.B., Henner, D., Wong, W.L., Rowland, A.M., Kotts,

C, Carver, M.E., and Shepard, H.M. (1992). Humanization of an anti-pl85HER2 antibody for human cancer therapy. Proc Natl Acad Sci U S A 89, 4285-4289.

Chiu, Y.L., and Rana, T.M. (2002). RNAi in human cells: basic structural and functional features of small interfering RNA. Mol Cell 10, 549-561.

Duncan, R.E., Sarkadi-Nagy, E., Jaworski, K., Ahmadian, M., and Sul, H.S. (2008), Identification and functional characterization of adipose-specific phospholipase A2 (AdPLA). J Biol Chem 283,

25428-25436.

Elbashir, S.M., Harborth, J., Lendeckel, W., Yalcin, A., Weber, ., and Tuschl, T. (2001 ). Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells. Nature 411, 494-498. Feuerer, M., Herrero, L., Cipolletta, D., Naaz, A., Wong, J., Nayer, A., Lee, J., Goldfine, A.B,,

Benoist, C, Shoelson, S., et al. (2009). Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters. Nat Med 15, 930-939.

Fire, A., Xu, S., Montgomery, M.K., Kostas, S.A., Driver, S.E., and Mello, G.C. (1998). Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature 391, 806- 81 1.

Gregor, M.F., and Hotamisligil, G.S. (201 1). Inflammatory mechanisms in obesity. Annu Rev

Immunol 29, 415-445.

Guilherme, A., Virbasius, J.V., Puri, V., and Czech, M.P. (2008). Adipocyte dysfunctions linking obesity to insulin resistance and type 2 diabetes. Nat Rev Mol Cell Biol 9, 36Ί-ΪΊΊ.

Hansford, .A., Reid, R.C., Clark, C.I., Tyndall, J.D., Whitehouse, M.W., Guthrie, T., McGeary, R.P., Schafer, K., Martin, J.L., and Fairlie, D.P. (2003). D-Tyrosine as a chiral precusor to potent inhibitors of human nonpancreatic secretory phospholipase A2 (Ila) with antiinflammatory activity. Chembiochem 4, 181-185. Horng, T., and Hotamisligil, G.S. (2011). Linking the inflammasome to obesity-related disease. Nat Med /7, 164-165.

Hotamisligil, G.S. (2006). Inflammation and metabolic disorders. Nature 444, 860-867.

Iyer, A., Fairlie, D.P., Prins, J.B., Hammock, B.D., and Brown, L. (2010). Inflammatory lipid mediators in adipocyte function and obesity. Nat Rev Endocrinol 6, 71-82.

Jaworski, K., Ahmadian, M., Duncan, R.E., Sarkadi-Nagy, E., Varady, K.A., Hellerstein, M.K., Lee,

H.Y., Samuel, V.T., Shu!man, G.I., Kim, K.H., et al. (2009a). AdPLA ablation increases lipolysis and prevents obesity induced by high-fat feeding or leptin deficiency. Nat Med 15, 159-168. Jaworski, K., Ahmadian, M., Duncan, R.E., Sarkadi-Nagy, E., Varady, K.A., Hellerstein, M.K., Lee, H.Y., Samuel, V.T., Shulman, G.I., Kim, K.H., et al (2009b). AdPLA ablation increases lipolysis and prevents obesity induced by high-fat feeding or leptin deficiency. Nature medicine 15, 159-

168.

Jones, P.T., Dear, P.H., Foote, J., Neuberger, M.S., and Winter, G. (1986). Replacing the

complementarity-determining regions in a human antibody with those from a mouse. Nature 321, 522-525.

Kim, S., and Moustaid-Moussa, N. (2000). Secretory, endocrine and autocrine/paracrine function of the adipocyte. J Nutr 130, 31 10S-3115S.

Kosteli, A , Sugaru, E., Haemmerle, G., Martin, J.F., Lei, J., Zechner, R., and Ferrante, A.W., Jr.

(2010). Weight loss and lipolysis promote a dynamic immune response in murine adipose tissue. J Clin Invest 120, 3466-3479.

Langin, D. (2006). Adipose tissue lipolysis as a metabolic pathway to define pharmacological strategies against obesity and the metabolic syndrome. Pharmacol Res 53, 482-491.

Lappas, M., Munns, M.J., King, R.G., and Rice, G.E. (2001). Antisense oligonucleotide inhibition of type II phospholipase A2 expression, release and activity in vitro. Placenta 22, 418-424.

Lee, N.S., Dohjima, T., Bauer, G., Li, H., Li, M.J., Ehsani, A., Salvaterra, P., and Rossi, J. (2002).

Expression of small interfering RNAs targeted against HIV-l rev transcripts in human cells, Nat

Biotechnol 20, 500-505.

Levick, S., Loch, D., Rolfe, B., Reid, R.C., Fairlie, D.P., Taylor, S.M., Brown, L. (2006) Antifibrotic activity of an inhibitor of group IIA secretory phospholipase A2 in young spontaneously hypertensive rats. J Immunol. 776(1 1),7000-7.

Liu, J., Divoux, A., Sun, J., Zhang, J., Clement, K., Glickman, J.N., Sukhova, G.K., Wolters, P.J., Du, J., Gorgun, C.Z., et al. (2009). Genetic deficiency and pharmacological stabilization of mast cells reduce diet-induced obesity and diabetes in mice. Nat Med 75, 940-945.

Mater, M.K., Thelen, A.P., and Jump, D.B. (1999). Arachidonic acid and PGE2 regulation of hepatic lipogenic gene expression. J Lipid Res 40, 1045-1052.

McManus, M.T., Petersen, CP., Haines, B.B., Chen, J., and Sharp, P.A. (2002). Gene silencing using micro-RNA designed hairpins. Rna 8, 842-850. Morrison, S.L., Johnson, M.J., Herzenberg, L.A., and Oi, V.T. (1984). Chimeric human antibody molecules: mouse antigen-binding domains with human constant region domains. Proc Natl Acad

Sci U S A S/, 6851-6855.

Nishimura, S., Manabe, I., Nagasaki, M., Eto, K., Yamashita, H., Ohsugi, M., Otsu, M., Hara, K., Ueki, K., Sugiura, S., et al. (2009). CD8+ effector T cells contribute to macrophage recruitment and adipose tissue inflammation in obesity. Nat Med 15, 914-920.

Orlandi, R., Gussow, D.H., Jones, P.T., and Winter, G. (1989). Cloning immunoglobulin variable domains for expression by the polymerase chain reaction. Proc Natl Acad Sci U S A 86, 3833-

3837.

Paddison, P.J., Caudy, A.A., Bernstein, E., Hannon, G.J., and Conklin, D.S. (2002). Short hairpin

RNAs (shRNAs) induce sequence-specific silencing in mammalian cells. Genes Dev 16, 948-958. Panchal, S.K., Poudyal, H., Iyer, A., Nazer, R., Alam, A., Diwan, V., Kauter, K., Sernia, C, Campbell, F., Ward, L., et al. (201 1). High-carbohydrate high-fat diet-induced metabolic syndrome and cardiovascular remodeling in rats. J Cardiovasc Pharmacol 57, 51-64.

Paul, CP., Good, P.D., Winer, I., and Engelke, D.R. (2002). Effective expression of small interfering RNA in human cells. Nat Biotechnol 20, 505-508.

Plasterk, R.H., and Ketting, R.F. (2000). The silence of the genes. Curr Opin Genet Dev 10, 562-567. Raddatz, K., Turner, N., Frangioudakis, G., Liao, B.M., Pedersen, D.J., Cantley, J., Wilks, D., Preston, E., Hegarty, B.D., Leitges, M., et al. (201 1). Time-dependent effects of Prkce deletion on glucose homeostasis and hepatic lipid metabolism on dietary lipid oversupply in mice. Diabetologia 54, 1447-1456.

Red Eagle, A., and Chawla, A. (2010). In obesity and weight loss, all roads lead to the mighty macrophage. J Clin Invest 120, 3437-3440.

Reddy, S.T., and Herschman, H.R. (1996). Transcellular prostaglandin production following mast cell activation is mediated by proximal secretory phospholipase A2 and distal prostaglandin synthase 1.

J Biol Chem 271, 186-191.

Reynolds, L.J., Hughes, L.L., and Dennis, E.A. (1992). Analysis of human synovial fluid

phospholipase A2 on short chain phosphatidylcholine-mixed micelles: development of a spectrophotometric assay suitable for a microtiterplate reader. Anal Biochem 204, 190-197.

Sandhu, J.S. (1992). Protein engineering of antibodies. Crit Rev Biotechnol 12, 437-462.

Scott, D.L., White, S.P., Browning, J.L., Rosa, J.J., Gelb, M.H., and Sigler, P.B. (1991). Structures of free and inhibited human secretory phospholipase A2 from inflammatory exudate. Science 254,

1007-1010.

Singer, II, Kawka, D.W., DeMartino, J.A., Daugherty, B.L., Elliston, K.O., Alves, K., Bush, B.L., Cameron, P.M., Cuca, G.C., Davies, P., et al (1993). Optimal humanization of 1B4, an anti-CDl 8 murine monoclonal antibody, is achieved by correct choice of human V-region framework sequences. Journal of immunology 150, 2844-2857. Strong, P., Coleman, R.A., and Humphrey, P.P. (1992). Prostanoid-induced inhibition of lipolysis in rat isolated adipocytes: probable involvement of EP3 receptors. Prostaglandins 43, 559-566.

Suen, J.Y., Gardiner, B., Grimmond, S., and Fairlie, D.P. (2010). Profiling gene expression induced by protease-activated receptor 2 (PAR2) activation in human kidney cells. PLoS One 5, el 3809. Sui, G., Soohoo, C, Affar el, B., Gay, F., Shi, Y., and Forrester, W.C. (2002). A DNA vector-based RNAi technology to suppress gene expression in mammalian cells. Proc Natl Acad Sci U S A 99, 5515-5520.

Thwin, M.M., Satyanarayanajois, S.D., Nagarajarao, L.M., Sato, ., Arjunan, P., Ramapatna, S.L., Kumar, P.V., and Gopa!akrishnakone, P. (2007). Novel peptide inhibitors of human secretory phospholipase A2 with antiinflammatory activity: solution structure and molecular modeling. J Med Chem 50, 5938-5950.

Tuschl, T. (2002). Expanding small RNA interference. Nat Biotechnol 20, 446-448.

Van Gaal, L.F., Mertens, I.L., and De Block, C.E. (2006). Mechanisms linking obesity with

cardiovascular disease. Nature 444, 875-880.

Wery, J.P., Schevitz, R. W., Clawson, D.K., Bobbitt, J.L., Dow, E.R., Gamboa, G., Goodson, T., Jr., Hermann, R.B., Kramer, R.M., McClure, D.B., et al. (1991). Structure of recombinant human rheumatoid arthritic synovial fluid phospholipase A2 at 2.2 A resolution. Nature 352, 79-82. Yu, J.Y., DeRuiter, S.L., and Turner, D.L. (2002). RNA interference by expression of short-interfering RNAs and hairpin RNAs in mammalian cells. Proc Natl Acad Sci U S A 99, 6047-6052.

Zeng, Y., Wagner, E.J., and Cuilen, B.R. (2002). Both natural and designed micro RNAs can inhibit the expression of cognate mRNAs when expressed in human cells. Mol Cell 9, 1327-1333.