BACKGROUND OF THE INVENTION The andiogen receptor ("AR") is a ligand-activated transcriptional regulatory protein that mediates induction of male sexual development and function through its activity with endogenous andiogens. Androgens are generally known as the male sex hormones The androgenic hormones aie steroids which are produced in the body by the testes and the cortex of the adrenal gland oi can be synthesized in the labotatory. Androgenic steroids play an important role in many physiologic processes, including the development and maintenance of male sexual chatacteristics such as muscle and bone mass, piostate growth, spermatogenesis, and the male hair pattern (Matsumoto, Endocrinol Met Clin N. Am 23:857-75 (1994)) The endogenous steroidal andiogens include testosterone and dihydrotestosterone ("DHT") Testosterone is the principal steroid secieted by the testes and is the primary circulating androgen found in the plasma of males Testosterone is converted to DHT by the enzyme 5 alpha-reductase in many peripheral tissues, DHT is thus thought to serve as the intracellular mediator for most androgen actions (Zhou, et al.. Molec. Endocrinol 9:208-18 (1995)). Othei steroidal androgens include esteis of testosterone, such as the cypionate, propionate, phenylpropionate, cyclopentylpropionate, isocarpoiate, enanthate, and decanoate esters, and other synthetic androgens such as 7-Methyl-Nortestosterone ("MENT') and its acetate ester (Sundaram ct al , "7 Alpha-Memyl-Nortestosteione(MENT): The Optimal Andiogen For Male Contraception," Ann. Med,, 25:199-205 (1993) ("Sundaram"). Because the AR is involved in male sexual development and function, the AR is a likely target for effecting male contraception or oilier forms of hormone replacement therapy.

[002] BMD (bone mineral density decreases with age in both males and females. Decreased amounts of bone mineral content (BMC) and BMD correlate with decreased bone strength and predispose patients to fracture.

[003] Osteoporosis is a systemic skeletal disease, characterized by low bone mass and deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture. In the U.S., the condition affects more than 25 million people and causes more than 1.3 million fractures each year, including 500,000 spine, 250,000 hip and 240,000 wrist fractures annually. Hip fractures are the most serious consequence of osteoporosis, with 5-20% of patients dying within one year, and over 50% of survivors being incapacitated. The elderly are at greatest risk of osteoporosis, and the problem is therefore predicted to increase significantly with the aging of the population.. Worldwide fracture incidence is forecasted to increase three-fold over the next 60 years, and one study estimated that there will be 4.5 million hip fractures worldwide in 2050,

[004] Women are at greater risk of osteoporosis than men. Women experience a sharp acceleration of bone loss during the five years following menopause. Other factors that increase the risk include smoking, alcohol abuse, a sedentary lifestyle and low calcium intake. However, osteopoiosis also occurs frequently in males. It is well established that the bone mineral density of males decrease with age. Decreased amounts of bone mineial content and density correlates with decreased bone strength, and predisposes to fracture. The molecular mechanisms underlying the pleiotropic effects of sex- hormones in non-reproductive tissues are only beginning to be understood, but it is clear that physiologic concentrations of androgens and estrogens play an important role in maintaining bone homeostasis throughout the life-cycle. Consequently, when androgen or estrogen deprivation occurs there is a resultant increase in the rate of bone remodeling that tilts the balance of resorption and formation to the favor of resorption that contributes to the overall loss of bone mass. In males, the natural decline in sex- hormones at maturity (direct decline in androgens as well as lower levels of estrogens derived from peripheral aromatization of androgens) is associated with the frailty of bones. This effect is also observed in males who have been castrated,

[005] Muscle wasting refers to Hie progressive loss of muscle mass and/or to the progressive weakening and degeneration of muscles, including the skeletal or voluntary muscles, which control movement, cardiac muscles, which control the heart (cardiomyopathies), and smooth muscles. Chronic muscle wasting is a chronic condition (i.e. persisting over a long period of time) characterized by progressive loss of muscle mass, weakening and degeneration of muscle.

[006] The loss of muscle mass that occurs during muscle wasting can be characterized by a muscle protein degradation by catabolism. Protein catabolism occurs because of an unusually Wgh rate of protein degradation, an unusually low rate of protein synthesis, or a combination of both. Muscle protein catabolism, whether caused by a high degree of protein degradation or a low degree of protein synthesis, leads to a decrease in muscle mass and to muscle wasting.

[007] Muscle wasting is associated with chronic, neurological, genetic or infectious pathologies, diseases, illnesses or conditions. These include Muscular Dystrophies such as Duchemie Muscular Dystrophy and Myotonic Dystrophy; Muscle Atrophies such as Post-Polio Muscle Atrophy (PPMA); Cachexias such as Cardiac Cachexia, AIDS Cachexia and Cancer Cachexia, malnutrition, Leprosy, Diabetes, Renal Disease, Chronic Obstructive Pulmonary Disease (COPD), Cancer, end stage Renal failure, Sarcopenia, Emphysema, Osteomalacia, HIV Infection, AIDS, and Cardiomyopathy.

[008] In addition, other circumstances and conditions are linked to and can cause muscle wasting. These include chronic lower back pain, advanced age, central nervous system (CNS) injury, peripheral nerve injury, spinal cord injury, chemical injury, central nervous system (CNS) damage, peripheral nerve damage, spinal cord damage, chemical damage, bums, disuse deconditioning that occurs when a limb is immobilized, long term hospitalization due to illness or injury, and alcoholism,

[009] An intact androgen receptor (AR) signaling pathway is crucial for appropriate development of skeletal muscles. Furthermore, an intact AR-signaling pathway increases lean muscle mass, muscle strength and muscle protein synthesis.

[0010] Muscle wasting, if left unabated, can have dire health consequences. For example, the changes that occur during muscle wasting can lead to a weakened physical state that is detrimental to an individual's health, resulting in increased susceptibility to infraction and poor performance status. In addition, muscle wasting is a strong predictor of morbidity and mortality in patients suffering from cachexia and AIDS.

Innovative approaches are urgently needed at both the basic science and clinical levels to prevent and treat osteoporosis and other bone-related disorders and muscle wasting, in paiticular chronic muscle wasting. The present invention is directed to satisfying this need.

SUMMARY OF THE INVENTION

[0012] In one embodiment, the present invention provides, a selective androgen receptor modulator (SARM) compound or its prodrug, analog, isomer, metabolite, derivative, pharmaceutically acceptable salt, pharmaceutical product, polymorph, crystal, impurity, N-oxide, hydrate or any combination thereof, represented by a structure of formula (I): wherein X is O; Z is NO2, CN, COR, or CONHR; Y is I, CF3, Br, Cl, F or Sn(R)3; Q is CN. T is OH, OR, -NHCOCH3, NHCOR or OC(O)R R is alkyl, haloalkyl. dihaloalkyl, trihaloalkyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, halogen, alkenyl or OH; and R, is CH3, CH2F, CHF2, CF3, CH2CH3, or CF2CF3.

[0013] In another embodiment, the present invention provides a selective androgen

receptor modulator (SARM) compound or its prodrug, analog, isomer, metabolite,

derivative, pharmaceutically acceptable salt, pharmaceutical product, polymorph,

crystal, impurity, N-oxide, hydrate or any combination thereof, represented by a

structure of formula (III):

(III)

[0014] In another embodiment, this invention provides a selective androgen receptor

modulator (SARM) compound or its piodrug, analog, isomer, metabolite, derivative,

pharmaceutically acceptable salt, pharmaceutical product, polymorph, crystal,

impurity, N-oxide, hydrate or any combination thereof, represented by a structure of

formula (IV): IV wherein X is O; T iS OH5 OR5 NHCOCH3, NHCOR or OC(O)R; Z is H5 alkyl, NO2, CN5 COOH5 COR5 NHCOR or CONHR; Y is hydrogen, alkyl. , CF3, halogen hydroxy-alkyl or alkyl aldehyde; A is a group selected from:

wherein R2, R3, R4, Rs, R6 are independently H, halogen, CN, NO2, NHCOCF3; R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH2F5 CHF2, CF3, CF2CF3, aryl, phenyl, halogen, alkenyl or OH; and Ri is CH3, CH2F5 CHF2, CF3, CH2CH3, or CF2CF3.

[OO 15] In one embodiment, according to this aspect of the invention, X is O, or in

another embodiment, T is OH5 or in another embodiment, Rl is CH3, or in another

embodiment, Z is NO2, or in another embodiment, Z is CN, or in another

embodiment, R2, R3, R5, R6 are hydrogens and R4 is NHC0CF3, or in another

embodiment, R.2, RJ5 R5, R6 are hydrogens and R4 is F, or in another embodiment,

R25 R3, R5, R6 are hydrogens, or in another embodiment, Z is in the para position, or in another embodiment, Y is in the meta position, or in another embodiment, any combination thereof'

[0016] In another embodiment, the invention provides a pharmaceutical composition comprising the SARM compounds of formula (I), (III) or (IV) and a suitable carrier or diluent.

[0017] In another embodiment, the invention provides a use of the compound of formula (I), (III) or (IV), or a composition comprising the same, in treating a subject having a bone-related disorder.

[0018] In another embodiment, the invention provides a use of the compound of formula (I), (III) or (IV) or a composition comprising the same, in increasing the strength of, or mass of a bone of a subject, or in promoting bone formation in a subject,

[0019] ϊn another embodiment, the invention provides a use of the compound of formula (I), (III) or (IV) for treating, preventing, suppressing, inhibiting or reducing the incidence of a muscle wasting disorder in a subject,

[0020] In another embodiment, the invention provides a use of the compound of formula (I), (III) or (IV) in increasing muscle performance, muscle size, muscle strength, or any combination thereof in a subject. [002I] In anothei embodiment, the invention provides a use of the compound of formula (I), (III) or (IV), or a composition comprising the same, in treating obesity or diabetes associated with a metabolic syndrome in a subject.

[0022] In another embodiment, the invention provides a use of the compound of formula (I), (III) or (FV), or a composition comprising the same, in promoting or speeding recovery following a surgical procedure.

[0023] In another embodiment, the invention provides a use of the compound of formula (I), (III) or (IV), oi a composition comprising the same, in promoting or suppressing spermatogenesis in a male subject.

BRIEF DESCRIPTION OF THE DRAWINGS

Fig l: Effect of SARMs, DHT and PTH on Differentiation of RaI Bone Marrow Cells

Towards Osteoblast Lineage.

Fig 2: Effect of SARMs, DHT and PTH on TRAP Positive Multinucleated

Osteoclasts

Fig 3: Femoral maximum load determined by 3-point bending of the femur.

Fig 4: Trabecular bone mineral density determined by pQCT analysis of the distal

femur.

Fig. 5: Pharmacology of compound III in intact rats. Fig 6: Organ weights from castrated, compound Ill-treated rats presented as a percentage of intact control. * P-value < 0.05 versus intact controls.

Fig 7: Organ weight maintenance dose-response curves for compound III in castrated rats, Emπx and ED50 values for the levator ani (closed triangles), prostate (open circles), and seminal vesicles (closed squares) weie obtained by nonlinear regression analysis using the sigmoid Emaχ model in WiriNonlin®.

Fig 8: Organ weights from castrated, Compound IIRieated rats piesented as a percentage of intact control * P-value < 0,05 versus intact controls.

Fig 9: Organ weight regrowth dose-response curves for compound III in castrated rats Emax and ED50 values for the levator ani (closed triangles), piostate (open ciicles), and seminal vesicles (closed squares) were obtained by nonlinear regression analysis using the sigmoid Emax model in WiriNonlin©.

Fig 10: Plasma concentration-time profile for compound III in healthy human volunteers with oral dose in PEG300.

Fig 11: Plasma-concentration-time profiles of compound III solution vs, solid oral dosage forms.

Fig 12: Plasma-concentration-time profiles of various compound III dosage forms at 30 mg. Fig 13: Dose versus AUCo-inf for oral solutions (G 100401)

Fig 14; Dose versus Cmaχ for oral solutions.

'JtS: Cholesterol reduction by compound III in rats.

DETAILED DESCRIPTION OF THE PRESENT INVENTION [001] In the following detailed description, numerous specific details are set forth in order to provide a thorough understanding of the invention. However, it will be understood by those skilled in the art that the present invention may be practiced without these specific details, In other instances, well-known methods, procedures, and components have not been described in detail so as not to obscure the present invention.

[002] In one embodiment the present invention provides, a selective androgen receptor modulator (SARM) compound or its prodrug, analog, isomer, metabolite, derivative, pharmaceutically acceptable salt, pharmaceutical product, polymorph, crystal, impurity, N-oxide, hydrate or any combination thereof, represented by a structure of formula (I):

I

wherein X is O; Z is NO2, CN3 COR, or CONHR; Y iS l5 CF35 Br5 Cl3 F Or Sn(R)3; Q is CN. T iS OH3 OR5 -NHCOCH35 NHCOR Or OC(O)R R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH2F, CHF2, CF3, CF2CF3, aiyl, phenyl, halogen, alkenyl oi OH; and R, is CH3, CH2F5 CHF2, CF3, CH2CH3, or CF2CF3.

[003] hi another embodiment the present invention provides a SARM represented

by a structuie of formula (II):

(")

wherein X is O; Z is NO2, CN5 COR, or CONHR; Y is I, CF3, Br, Cl5 F or Sn(R)3; R is an alkyl group or OH; and Q is CN.

[004] In one embodiment, the invention piovides a selective androgen receptor

modulator (SARM) compound or its prodrug, analog, isomer, metabolite, derivative,

pharmaceutically acceptable salt, pharmaceutical product, polymorph, crystal, impurity, N-oxide, hydrate or any combination thereof, represented by a structure of formula (III):

(III) [005] In another embodiment, this invention provides a selective androgen receptor modulator (SARM) compound or its prodrug, analog, isomer, metabolite, derivative, pharmaceutically acceptable salt, pharmaceutical product, polymorph, crystal, impurity, N-oxide, hydrate or any combination thereof, represented by a structure of formula (TV):

ΓV Wherein X is O; T is OH, OR, NHCOCH3, NHCOR or OC(O)R; Z is H, alkyl, NO2, CN, COOH5 COR, NHCOR or CONHR; Y is hydrogen, alkyl, CF3, halogen, hydroxy-alkyl or alkyl aldehyde;

A is a group selected from:

wherein R2, R3, R4, R5, R6 are independently H5 halogen, CN, NO2, NHCOCF3; R is alley], haloalkyl, dihaloalkyl, tiϊhaloalkyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, halogen, alkenyl or OH; and R1 is CH3, CH2F, CHF2, CF3, CH2CH3, or CF2CF3.

[006] In one embodiment, according to this aspect of the invention, X is O, or in another embodiment, T is OH5 or in another embodiment, Rl is CH3, or in another embodiment, Z is NO2, or in another embodiment, Z is CN, or in another embodiment, R2, R3, R5, R6 are hydrogens and R4 is NHCOCF3, or in another embodiment, R2, R3, R5, R6 are hydrogens and R4 is F, or in another embodiment, R2, R3, R5, R6 aie hydiogens, or in another embodiment, Z is in the para position, or in another embodiment, Y is in the meta position, or' in another embodiment, any combination thereof ,

[007] In one embodiment, the invention provides a pharmaceutical composition, including compounds of formula (I), (II), (III) or (TV) or its prodiug, analog, isomer, metabolite, derivative, pharmaceutically acceptable salt, pharmaceutical product, polymorph, crystal, impurity, N-oxide, hydrate or any combination thereof, and a suitable carrier or diluent. [008] An "allcyl" group refers, in one embodiment, to a saturated aliphatic hydrocarbon, including straight-chain, branched-chain and cyclic alkyl groups. In one embodiment, the allcyl group has 1-12 caibons. In another embodiment, the alkyl group has 1-7 caibons. In another embodiment, the alkyl group has 1-6 carbons, In another embodiment, the alkyl group has 1-4 carbons. The allcyl group may be unsubstituted or substituted by one or more gioups selected from halogen, hydroxy, alkoxy carbonyl, amido, aJkylamido, dialkylamido, nitro, amino, alkyiamino, dialkylamino, carboxyl, thio and thioallcyl

[009] An "alkenyl" group refers, in another embodiment, to an unsaturated hydrocarbon, including straight chain, branched chain and cyclic groups having one or more double bond. The alkenyl group may have one double bond, two double bonds, three double bonds etc. Examples of alkenyl groups are ethenyl, propenyl, butenyl, cyclohexenyl etc. The alkenyl group may be unsubstituted or substituted by one or more groups selected from halogen, hydroxy, alkoxy carbonyl, amido, alkylamido, dialkylamido, nitro, amino, alkylamino, dialkylamino, carboxyl, thio and thioalkyl.

[0010] A "haloallcyl" group refers to an alkyl group as defined above, which is substituted by one or more halogen atoms, in one embodiment by F, in another embodiment by Cl, in another embodiment by Br , in another embodiment by I.

[0011] An "aryl" group refers to an aromatic group having at least one carbocyclic aromatic group or heterocyclic aromatic group, which may be unsubstituted or substituted by one or more groups selected from halogen, haloalkyl, hydroxy, alkoxy carbonyl, amido, alkylamido, dialkylamido, nilro, amino, alkylamino, dialkylamino, carboxy or tliio or Uiioallcyl Nonlimiting examples of aryl rings are phenyl, naphlhyl, pyranyl, pyrrυlyl, pyrazinyl. pyrimidinyl, pyrazolyl, pyridinyl, furanyl, thiophenyl, tliiazolyl, imidazolyl, isoxazolyl, and the like,

[0012] A "hydioxyl" group refers to an OH group. It is understood by a person skilled in the art that when T in the compounds of the present invention is OR, R is not OH.

[0013] to one embodiment, the term "halo" or "halogen" refers to in one embodiment to F, in another embodiment to Cl5 in another embodiment to Br or in another embodiment to L

[0014] An "arylalkyl" group refers, in another embodiment, to an alley! bound to an aryl, wherein alkyl and aryl are as defined above An example of an arylalkyl group is a benzyl gioup

[0015] In one embodiment, this invention provides a SARM compound and/or , analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydiate, N-oxide, prodrug, polymorph, impurity or crystal oi combinations thereof. In one embodiment, this invention provides an analog of the SARM compound In another embodiment, this invention provides a derivative of the SARM compound. In anothei embodiment, this invention provides an isomer of the SARM compound. In another embodiment, this invention provides a metabolite of the SARM compound. In another embodiment, this invention provides a pharmaceutically acceptable salt of the SARM compound In another embodiment, this invention provides a pharmaceutical product of the SARM compound. In another embodiment, this invention provides a hydrate of the SARM compound. In another embodiment, this invention provides an N- oxide of the SARM compound. In another embodiment, this invention provides a prodrug of the SARM compound, In another embodiment, this invention provides a polymorph of the SARM compound- In anothei embodiment, this invention provides a crystal of the SARM compound In another embodiment, this invention provides an impurity of the SARM compound. In another embodiment, this invention provides composition comprising a SARM compound, as described herein, or, in another embodiment, a combination of an analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, prodrug, polymorph, impurity or crystal of the SARM compounds of the present invention.

[0016] In one embodiment, the term "isomer" includes, but is not limited to, optical isomers and analogs, structural isomers and analogs, confoimatioπal isomers and analogs, and the like

[0017] hi one embodiment, the term "isomer"' is meant to encompass optical isomers of the SARM compound It will be appieciated by those skilled in the ail that the SARMs of the present invention contain at least one chiral center. Accordingly, the SARMs used in the methods of the present invention may exist in, and be isolated in, optically-active or racemic forms. Some compounds may also exhibit polymorphism It is to be understood thai the present invention encompasses any racemic, optically-active, polymorphic, oi stereroisomeric form, or mixtures thereof, which form possesses properties useful in the tieatment of androgen-related conditions described herein, hi one embodiment, the SARMs are the pure (R)-isomeis. In another embodiment, the SARMs are the pure (S)- isomers. hi another embodiment, the SARMs are a mixture of the (R) and the (S) isomers In another embodiment, the SARMs ate a racemic mixture comprising an equal amount of the (R) and the (S) isomers It is well known in the art how to prepare optically-active forms (for example, by resolution of the iacemic form by recrystallizalion techniques, by synthesis fiorn optically-active starting materials, by chiral synthesis, oi by chromatographic separation using a chiral stationary phase).

[0018] The invention includes "pharmaceutically acceptable salts" of the SARMs of this invention, which may be ptoduced, in one embodiment, using an amino-substituted SARM and an organic and inorganic acids, for example, citric acid and hydiochloiic acid. Pharmaceutically acceptable salts can be prepared, from the phenolic compounds, in other embodiments, by treatment with inorganic bases, for example, sodium hydi oxide. In another embodiment, esters of the phenolic compounds can be made with aliphatic and aromatic carboxylic acids, for example, acetic acid and benzoic acid esteis.

[0019] The invention also includes N-oxides of the amino substituents of the SARMs described herein.

[0020] This invention provides derivatives of the SARM compounds, hi one embodiment, "derivatives" includes but is not limited to ethei derivatives, acid derivatives, I S amide derivatives, ester derivatives and the like In another embodiment, this invention further includes hydrates of the SARM compounds. In one embodiment, "hydrate" includes but is not limited to hemihydrate, monohydrate, dihydrate, trihydrate and the like,

[0021] This invention provides, in other embodiments, metabolites of the SARM compounds. In one embodiment, "metabolite" means any substance produced from another substance by metabolism or a metabolic process

[0022] TWs invention provides, in other embodiments, pharmaceutical products of the SARM compounds. The term "pharmaceutical product" refers, in other embodiments, to a composition suitable for pharmaceutical use (pharmaceutical composition), for example, as described herein.

Selective Androgen Receptor Modulators (SARMS)

[0023] Selective androgen ieceptor modulators (SARMs) are a class of androgen receptor targeting agents (ARTA), which demonstrate androgenic and anabolic activity of a nonsteroidal ligand for the androgen receptor. These novel agents are useful in males for the treatment of a variety of hormone-related conditions such as sexual dysfunction, decreased sexual libido, erectile dysfunction, hypogonadism, sarcopenia, osteopenia, osteoporosis, alterations in cognition and mood, depression, anemia, hair loss, obesity, benign prostate hyperplasia and/or prostate cancer. Furthei, SARMs are useful for oral testosterone replacement therapy, and imaging prostate cancer. In addition, SARMs are useful in females for the tieatment of a variety of hormone-related conditions including, such as sexual dysfunction, decreased sexual libido, hypogonadism, sarcopenia, osteopenia, osteoporosis, alterations in cognition and mood, depression, anemia, hair loss, obesity, endometriosis, breast cancer, uterine cancer and ovarian cancer.

[0024] As contemplated herein, this invention provides a class of compounds which are Selective Androgen Receptor Modulator (SARM) compounds. These compounds, which are useful in preventing and treating muscle wasting disorders and bone related disorders are classified as androgen receptor agonists (AR agonists), partial agonists or androgen receptor antagonists (AR antagonists).

[0025] A receptor agonist is a substance which binds receptors and activates them. A receptor partial agonist is a substance which binds receptor and partially activate mem. A receptor antagonist is a substance which binds receptors and inactivates mem. As demonstrated herein, the SARM compounds of the present invention may, in some embodiments, have a tissue-selective effect, wherein, for example, a single agent is an agonist, partial agonist and/or antagonist, depending on the tissue in which the receptor is expressed. For example, the SARM compound may stimulate muscle tissue and concurrently inhibit prostate tissue, In one embodiment, the SARMs which are useful in treating and preventing muscle wasting disorders are AR agonists, and are, therefore, useful in binding to and activating the AR hi another embodiment, the SARMs are AR antagonists, and are, therefore, useful in binding to and inactivating the AR. Assays to determine whether the compounds of the present invention are AR agonists or antagonists are well known to a person skilled in the art. For example, AR agonistic activity can be determined by monitoring the ability of the SARM compounds to maintain and/or stimulate the growth of AR containing tissue such as prostate and seminal vesicles, as measured by weight. AR antagonistic activity can be determined by monitoring the ability of the SARM compounds inhibit the growth of AR containing tissue.

In yet another embodiment, the SARM compounds of the present invention can be classified as partial AR agonist/antagonists, The SARMs are AR agonists in some tissues, to cause increased transcription of AR-responsive genes (e.g. muscle anabolic effect). In other tissues, these compounds serve as competitive inhibitors of testosterone/DHT on the AR to prevent agonistic effects of the native andiogens. The term SARM or selective androgen receptor modulator refers, in one embodiment, to a compound which modulates androgen receptor activity. In one embodiment, the SARM is an agonist, or in another embodiment, an antagonist.

[0026] In one embodiment, the SARM will have antagonist activity in a gonad of a subject, and agonist activity peripherally, such as, for example, in muscle. Such activity was demonstrated herein, in terms of effects on piostate tissue versus mat of levator ani muscle tissue, as exemplified in Figure 3, 4 or 5.

[0027] In one embodiment, the SARM compounds of the present invention bind reveisibly or, in another embodiment, iπeversibly to the andiogen receptor. In one embodiment, the SARM compounds bind reversibly to the androgen receptor In another embodiment, the SARM compounds bind iπeversibly to the androgen leceptor. The compounds of the present invention may contain a functional group (affinity label) that allows alkylation of the androgen receptor (i e. covalent bond formation). Thus, in this case, the compounds bind irreversibly to the receptor and, accordingly, cannot be displaced by a steroid, such as the endogenous ligands DHT and testosterone.

[0028] In one embodiment, modulation of the androgen receptor refeis to the ability of the compound to stimulate or enhance signaling through the receptor, and any or, in anothei embodiment, all, downstream effects of receptor signal transduction.

[0029] In another embodiment, modulation of the androgen receptor iefeis to the ability of the compound to diminish oi abrogate signaling though the receptor, and any or, in another embodiment, all, downstream effects of receptor signal transduction.

[0030] In another embodiment, a SARM of this invention may interact with a homologue of an androgen receptor. In one embodiment, the term "homologue of an androgen receptor" refers to structurally or, in another embodiment, functionally related receptors, whose regulation is desired, hi one embodiment, the SARMs of this invention may interact with estrogen receptors, or, in another embodiment, other cell surface molecules which are involved in anabolic pathways, oi in another embodiment, steroidogenic pathways, or in another embodiment, metabolic pathways

[0031] In one embodiment, this invention also provides for a composition comprising a SARM, or in another embodiment, SARMs of this invention.

[0032] In one embodiment the composition is a pharmaceutical composition, which, in another embodiment is a pellet, a tablet, a capsule, micronized and non-micronized capsule, a solution, a suspension, an emulsion, an elixir, a gel, a cream, a suppository or a parenteral formulation.

[0033] In one embodiment, the micronized capsules comprise particles containing a SAEM of this invention, wherein the term "micionized" used herein refeis to paiticles having a particle size is of less than 100 microns, or in another embodiment, less than 50 microns, or in another embodiment, less than 35 microns, oi in another embodiment, less than 15 microns, or in another embodiment, less than 10 microns, or in anothei embodiment, less than 5 microns.

[0034] The pharmaceutical compositions may be administered in any effective, convenient mannei including, for instance, administiation by intr avascular- (i v.), intramuscular (Lm.), intranasal (Ln,), subcutaneous (s.c), sublingual, oral, rectal, intravaginal delivery, or by any means in which the recombinant virus/composition can be delivered to tissue (e.g., needle or catheter). Alternatively, topical administration may be desired for application to mucosal cells, for skin or ocular application. Another method of administration is via aspiration or aerosol formulation.

[0035] For administration to mammals, and particularly humans, it is expected that the physician will determine the actual dosage and duration of treatment, which will be most suitable for an individual and can vary with the age, weight and response of the particular individual, [0036] In one embodiment, the compositions for administration may be sterile solutions, or in other embodiments, aqueous or non-aqueous, suspensions or emulsions. In one embodiment, the compositions may comprise propylene glycol, polyethylene glycol, injectable organic esters, for example ethyl oleate, or cyclodextrins In another embodiment, compositions may also comprise wetting, emulsifying and/or dispersing agents. In another embodiment, the compositions may also comprise sterile water or any other sterile injectable medium.

[0037] In one embodiment, the compositions of this invention may include, a SARM of this invention or any combination thereof, together with one or more pharmaceutically acceptable excipients.

[0038] In one embodiment, "pharmaceutical composition" can mean a therapeutically effective amount of one oi more compounds of the present invention together with suitable excipients and/or carriers useful in the methods of this invention. In one embodiment the compositions will comprise a therapeutically effective amount of a SARM of this invention, hi one cmboidment, the term "therapeutically effective amount" may refer to that amount that provides a therapeutic effect for a given condition and administration regimen. In one embodiment, such compositions can be administered by any method known in the art

[0039] In one embodiment, the compositions of the present invention are formulated as oial or parenteral dosage forms, such as uncoated tablets, coated tablets, pills, capsules, powders, granulates, dispersions or suspensions In another embodiment, the compositions of the present invention are foimulated for intravenous administration. In another embodiment, the compounds of the present invention aie formulated in ointment, cream or gel form for transdermal administration. In another embodiment, the compounds of the piesent invention are formulated as an aerosol or spray for nasal application. In another embodiment, the compositions of the present invention are formulated in a liquid dosage form. Examples of suitable liquid dosage forms include solutions or suspensions in water, pharmaceutically acceptable fats and oils, alcohols or other organic solvents, including estei s, emulsions, syrups oi elixirs, solutions and/or suspensions

[0040] Suitable excipients and carriers may be, according to embodiments of the invention, solid or liquid and the type is generally chosen based on the type of administration being used. Liposomes may also be used to deliver the composition. Examples of suitable solid carriers include lactose, sucrose, gelatin and agar. Oral dosage forms may contain suitable binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents, and melting agents. Liquid dosage forms may contain, for example, suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, thickeners, and melting agents. Parenteral and intravenous foims should also include minerals and other materials to make them compatible with the type of injection or delivery system chosen. Of course, other excipients may also be used.

[0041] The SARMs of this invention may be administered at various dosages. In one embodiment, the SARM is administered at a dosage of 0.1 - 200 mg per day. In one embodiment, the SARM is administered at a dose of 0 1 - 10 mg, or in another embodiment, 0.1 - 25 mg, or in another embodiment, 0,1- 50 mg. or in another embodiment, 0.3 - 15 mg, or in another embodiment, 0.3 - 30 mg, or in another embodiment, 0.5 - 25 mg, or in another embodiment, 0.5 - 50 mg, or in another embodiment, 075 - 15 mg, or in another embodiment, 0J5 - 60 mg, or in anothei embodiment, 1 - 5 mg, or in another embodiment, 1 - 20 mg, or in another embodiment, 3 - 15 mg, or in another embodiment, 30 - 50 mg, or in another embodiment, 30 - 75 mg, or in another embodiment, 100 - 2000 mg.

[0042] The SARMs of mis invention may be administered at vaiious dosages. In one embodiment, the SARM is administered at a dosage of 1 mg. In another embodiment the SARM is administered at a dosage of 5mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg , 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg or 100 mg.

[0043] In one embodiment, the compounds and compositions of this invention may be used for any of the methods of this invention, as described herein. In one embodiment, use of a SARM or a composition comprising the same, will have utility in inhibiting, suppressing, enhancing or stimulating a desired response in a subject, as will be understood by one skilled in the art hi another embodiment, the compositions may further comprise additional active ingredients, whose activity is useful for the particular application for which the SARM compound is being administered.

[0044] In one embodiment, this invention provides for the use of a SARM compound of this invention, or its prodrug, analog, isomer, metabolite, derivative, pharmaceutically acceptable salt, pharmaceutical product, polymorph, crystal, impurity, N-oxide, hydrate or any combination thereof, for 1) treating a bone related disorder; 2) preventing a bone related disorder; 3) suppresing a bone related disorder; 4) inhibiting a bone related disorder1; 5) increasing a strength of a bone of a subject; 5) increasing a bone mass in a subject; 6) use for t osteoclastogenesis inhibition. In one embodiment the SARM compound is a compound of formula I, II, III or FV, as described herein.

[0045] In one embodiment, the bone related disorder is a genetic disorder, or in another embodiment, is induced as a result of a treatment regimen for a given disease. For example, and in one embodiment, the SARMs of this invention are useful in treating a bone-ielated disorder that arises as a result of androgen-deprivation therapy, given in response to prostate carcinogenesis in a subject.

[0046] In one embodiment, the present invention provides a use of SARM compound for preventing a bone-related disorder in a subject, In another embodiment, the present invention provides a use of SARM compound for suppressing a bone-related disorder in a subject. In another embodiment, the present invention provides a use of SARM compound for inhibiting a bone-related disorder in a subject, In another embodiment the SARM compound is of formula (I)5 (II), (III) or (TV), In another embodiment, the SARM compound is of formula (T), (II), (111) or1 (IV) or its prodrug, analog, isomer, metabolite, derivative, pharmaceutically acceptable salt, pharmaceutical product, polymorph, crystal, impurity, N-oxide, hydrate or any combination thereof.

[0047] hi one embodiment, the bone-related disorder is osteoporosis. In another embodiment, the bone-related disorder is osteopenia, In another' embodiment, the bone- related disordei is increased bone resorption. In another embodiment, the bone-related disorder is bone fracture. In another embodiment, the bone-related disorder is bone frailty. In anothei embodiment, the bone-related disorder is a loss of BMD. In another embodiment, the bone-related disorder is any combination of osteoporosis, osteopenia, increased bone resorption, bone fracture, bone fiailty and loss of BMD, Each disorder represents a sepaiate embodiment of the present invention,

[0048] "Osteoporosis" refers, in one embodiment, to a thinning of the bones with reduction in bone mass due to depletion of calcium and bone protein, In another embodiment, osteopoiosis is a systemic skeletal disease, characterized by low bone mass and deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fiacture. In osteoporotic patients, bone strength is abnoimal, in one embodiment, with a resulting increase in the risk of fracture, In another embodiment, osteoporosis depletes both the calcium and the protein collagen noπnally found in the bone, in one embodiment, resulting in either abnormal bone quality or decreased bone density. In another embodiment, bones that are affected by osteoporosis can fracture with only a minor fall or injury that noimally would not cause a bone fracture. The fracture can be, in one embodiment, either in the form of cracking (as in a hip fracture) or collapsing (as in a compression fracture of the spine) The spine, hips, and wrists are common areas of osteoporosis-induced bone fractures, although fiactures can also occur in othei skeletal areas. Unchecked osteoporosis can lead, in another embodiment, to changes in posture, physical abnormality, and decreased mobility. [0049] In one embodiment, the osteoporosis results from androgen deprivation. In another embodiment, the osteoporosis follows androgen deprivation. In another embodiment, the osteoporosis is primary osteoporosis. In another embodiment, the osteoporosis is secondary osteoporosis. In anothei embodiment, the osteoporosis is postmenopausal osteoporosis. In another embodiment, the osteoporosis is juvenile osteoporosis. In another embodiment, the osteoporosis is idiopathic osteoporosis. In another embodiment, the osteoporosis is senile osteoporosis.

[0050] In another embodiment, the primaiy osteoporosis is Type I primary osteoporosis, hi another embodiment, the primary osteoporosis is Type II primaiy osteoporosis. Each type of osteoporosis represents a separate embodiment of the present invention,

[0051] Osteoporosis and osteopenia are, in another embodiment, systemic skeletal diseases characterized by low bone mass and microarchitectuial deterioration of bone tissue. "Microarchitectural deterioration" refers, in one embodiment, to thinning of the trabeculae (defined below) and the loss of inter-trabecular connections in bone. In another embodiment, "osteoporosis" is defined as having a BMD 2 5 standaid deviations (SD) or more below the young adult mean, hi anothei embodiment, "osteoporosis" is defined as having a BMC 2,5 SD or more below the young adult mean. In another embodiment, "osteoporosis" is defined as having a BMD 2.0 SD or more below the young adult mean. In another embodiment, "osteoporosis" is defined as having a BMC 2.0 SD oi more below the young adult mean. In anothei embodiment, "osteoporosis" is defined as having a BMD 3.0 SD oi more below the young adult mean. In another embodiment, "osteoporosis" is defined as having a BMC 3 ,0 SD or more below the young adult mean. Each definition of osteoporosis or osteopenia represents a separate embodiment of the present invention.

[0052] In another embodiment, "osteoporosis" is defined as having a BMD 2.5 SD below the young adult mean. In another embodiment, "osteoporosis" is defined as having a BMC 2.5 SD below the young adult mean, In another embodiment, "osteoporosis" is defined as having a BMD 2.0 SD below the young adult mean, In another embodiment, "osteoporosis" is defined as having a BMC 2.0 SD below the young adult mean. In another embodiment, "osteoporosis" is defined as having a BMD 3.0 SD below the young adult mean. In another embodiment, "osteoporosis" is defined as having a BMC 3.0 SD below the young adult mean. Each definition of osteoporosis represents a separate embodiment of the present invention.

[0053] Methods for assessing osteoporosis and osteopenia are well known in the art. For example, in one embodiment, a patient's BMD, measured by densitometry and expressed in g/cm2, is compared with a "normal value," which is the mean BMD of sex- matched young adults at their peak bone mass, yielding a "T score." In another embodiment, Z-score, the amount of bone loss in a patient is compared with the expected loss for individuals of the same age and sex., In another embodiment, "osteoporosis" is defined as having a T score 2.5 SD or more below the young adult mean., In another embodiment, "osteoporosis" is defined as having a Z score 2.5 SD or more below the young adult mean* In another embodiment, "osteoporosis" is defined as having a T score 2.0 SD or more below the young adult mean, hi another embodiment, "osteoporosis" is defined as having a Z score 2 0 SD or more below the young adult mean, In another embodiment, "ostcopoiosis" is defined as having a T score 3.0 SD or more below the young adult mean, In another embodiment, "osteoporosis" is defined as having a Z score 3.0 SD or more below the young adult mean.

[0054] In another embodiment, "osteoporosis*5 is defined as having a T scoie 2,5 SD below the young adult mean. In another embodiment, "osteoporosis" is defined as having a Z score 2.5 SD below the young adult mean. In another embodiment, "osteoporosis" is defined as having a T scoie 20 SD below the young adult mean In another embodiment, "osteoporosis'" is defined as having a Z scoie 2.0 SD below the young adult mean, In another embodiment, "osteoporosis" is defined as having a T score 3.0 SD below the young adult mean. In another embodiment, "osteoporosis" is defined as having a Z score 3.0 SD below the young adult mean. Each definition of osteoporosis represents a separate embodiment of the piesent invention.

[0055] The term "BMD" is, in one embodiment, a measuied calculation of the true mass of bone. The absolute amount of bone as measured by BMD generally correlates with bone strength and its ability to bear weight By measuring BMD, it is possible to piedict fracture risk in the same manner that measuring blood pressure can help piedict the risk of stroke.

[0056] BMD, in one embodiment, can be measured by known BMD mapping techniques In one embodiment, bone density of the hip, spine, wrist, or calcaneus may be measured by a variety of techniques. The preferred method of BMD measurement is dual- energy x-iay densitometry (DEXA). BMD of the hip, anteio-posterioi (AP) spine, lateral spine, and wrist can be measured using this technology. Measurement at any site predicts overall risk of fracture, but information fiom a specific site is the best predictor of fracture at that site Quantitative computerized tomography (QCT) is also used to measure BMD of the spine. See for example, "Nuclear Medicine: "Quantitative Procedures" by Wahner H W, et al, published by Toionto Little, Brown & Co., 1983, pages 107-132; "Assessment of Bone Mineral Part 1," J Nucl Medicine, pp 1134-1141 (1984); and "Bone Mineral Density of The Radius" J Nucl Medicine 26: 13-39 (1985), Each method of measuring BMD represents a separate embodiment of the present invention.

[0057] "Osteopenia" refers, in one embodiment, to having a BMD or BMC between 1 and 2 5 SD below the young adult mean In another embodiment, "osteopenia" iefers to decreased calcification or density of bone. This term encompasses, in one embodiment, all skeletal systems in which such a condition is noted. Each definition or means of diagnosis of the disorders disclosed in the present invention repiesents a separate embodiment of the present invention,

[0058] hi one embodiment, the term "bone fracture" refers to a breaking of bones, and encompasses both vertebral and non-veitebral bone fiactures. The teπn "bone frailty" iefers, in one embodiment, to a weakened state of the bones that predisposes mem to fractures. [0059] In one embodiment, the bone-relaled disorder is treated with a SARM compound of this invention, or a combination thereof. In another embodiment, other bone-stimulating compounds can be provided to a subject, prior to, concurrent with or following administration of a SARM oi SARMs of this invention, hi one embodiment, such a bone stimulating compound may comprise natural or synthetic materials.

[0060] In one embodiment, the bone stimulating compound may comprise a bone morphogenetic protein (BMP), a growth factor, such as epidermal giowth factor (EGF), a fibroblast growth factor (FGF), a transforming growth factor (TGF-α or TGF-β), an insulin growth factor (IGF), a platelet-derived growth factor (PDGF) hedgehog proteins such as sonic, inώ'aπ and desert hedgehog, a hormone such as follicle stimulating hormone, paramyloid hormone, paramyloid hormone related peptide, activins, inhibins, fiϊzzled, fi'∑b or frazzled proteins, BMP binding proteins such as chordin and fetuin, a cytokine such as IL-3, IL-7, GM-CSF, a chemokine, such as eotaxin, a collagen, osteocalcin, osteonectin and others, as will be appreciated by one skilled in the ait

[0061 ] hi another embodiment, the compositions for use in treating a bone disorder of mis invention may comprise a SARM or SARMs of this invention, an additional bone stimulating compound, oi compounds, and osteogenic cells, In one embodiment, an osteogenic cell may be a stem cell or progenitor cell, which may be induced to differentiate into an osteoblast, hi another embodiment, the cell may be an osteoblast, [0062] In another embodiment, nucleic acids which encode bone-stimulating compounds may be administered to the subject, which is to be considered as pait of this invention

[0063] In one embodiment, the osteoporosis, osteopenia, increased bone resorption, bone fracture, bone frailty, loss of BMD, and other diseases or disorders of the present invention aie caused by a hormonal disorder, disruption or imbalance. In another embodiment, these conditions occur independently of a hormonal disorder, disruption or imbalance. Each possibility repiesents a separate embodiment of the present invention.

[0064] In one embodiment, the hormonal disorder, disruption or imbalance comprises an excess of a hormone, In another embodiment, the hormonal disorder, disruption or imbalance comprises a deficiency of a hormone. In one embodiment, the hormone is a steroid hormone. In another embodiment, the hormone is an estrogen. In another embodiment, the hormone is an androgen, In anothei embodiment, the hormone is a glucocorticoid. In another embodiment, the hormone is a corticosteroid.. In another embodiment, the hormone is Luteinizing Hormone (LH), In another embodiment, the hormone is Follicle Stimulating Hormone (FSH), In another embodiment, the hormone is any oilier hormone known in the ait. In another embodiment, the hormonal disorder, disruption or imbalance is associated with menopause. In another embodiment, hormone deficiency is a result of specific manipulation, as a byproduct of treating a disease or1 disorder in the subject. For example, the hormone deficiency may be a result of androgen depletion in a subject, as a therapy for prostate cancer in the subject, [0065] Each possibility represents a separate embodiment of the present invention.

[0066] In one embodiment, the invention provides a use of SARM compounds for increasing a strength of a bone of a subject. In another embodiment the SARM compound is of foimula (I), (H)5 (HI) or (IV). In another embodiment, the SARM compound is of formula (I), (IT), (III) or (IV) or its prodiug, analog, isomer, metabolite, derivative, pharmaceutically acceptable salt, pharmaceutical product, polymorph, crystal, impurity, N-oxide. hydrate or any combination thereof Thus, increasing a strength of a bone of a subject.

[0067] In another embodiment, the subject has an osteoporosis. In another embodiment the osteoporosis is hoimonally induced,

[0068] In one embodiment, the invention provides a use of SARM compounds for increasing a bone mass of a subject In another embodiment the SARM compound is of formula (I), (II), (IH) or (IV). In another embodiment, the SARM compound is of formula (I)5 (II), (DT) oi (IV) or its prodrug, analog, isomer, metabolite, derivative, pharmaceutically acceptable salt, pharmaceutical product, polymoiph, crystal, impurity, N-oxide, hydrate oi any combination theieof, or a composition comprising the same.

[0069] In another embodiment, the subject has osteopoiosis. In anothei embodiment the osteoporosis is hormoπally induced. In another embodiment the subject has sarcopenia or cachexia. In another embodiment the methods of this invention provide for increasing a bone mass in the subject, which is a cortical bone mass. In another embodiment the bone mass is trabeculai bone mass. In another embodiment the bone mass is a cancellous bone mass.

[0070] In one embodiment, the invention provides a use of SARM compounds for promoting bone formation. In another embodiment the SARM compound is of formula (I)5 (II), (III) or (IY). In another embodiment, the SARM compound is of formula (I), (II), (III) oi (IV) or its prodrug, analog, isomer, metabolite, derivative, pharmaceutically acceptable salt, pharmaceutical product, polymorph, crystal, impurity, N-oxide, hydrate or any combination thereof, oi a composition comprising the same.

[0071] In another embodiment, the SARM compound stimulates or enhances osteohistogenesis. In another embodiment, the said SARM compound inhibits osteoclast prolifϊcation.

[0072] In one embodiment, the invention provides for bone formation via osteoblast stimulation or enhanced proliferation. In one embodiment, the term "osteoblast" refers to cell which participates in bone-formation. In one embodiment, osteoblast involvement in bone formation may form the tissue and deposit minerals therein, giving bone its strength, In another embodiment, the invention provides for bone formation via suppiession of osteoclast induction, or1 in another embodiment, activity, In one embodiment, the term "osteoclast" refeis to a cell which participates in bone remodeling, and in particular in bone resorption. [0073] In one embodiment, bone diseases oi disorders are treated by the methods of this invention via stimulation of bone formation. In another embodiment, the treatments of this invention provide for maintenance of bone mass. Bone mass is maintained by a balance between the activity of osteoblasts that form bone and osteoclasts that break it down. In one embodiment, the compounds and methods of tliis invention provide a means whereby such a balance is maintained,

[0074] Figures 1-2 demonstrate that SARM compound III induced differentiation of bone marrow cells to osteoblasts yet inhibited osteoclast induction, indicating direct effects of SARMs on both osteoblasts and osteoclasts, which would be useful in increasing bone mass in osteoporotic patients.

[0075] In one embodiment, tliis invention provides use of a SARM compound of this invention, or its prodrug, analog, isomei, metabolite, derivative, pharmaceutically acceptable salt, pharmaceutical product, polymorph, crystal, impurity, N-oxide, hydrate or any combination thereof, for 1) treating a muscle wasting disorder; 2) preventing a muscle wasting disorder; 3) treating, preventing, suppressing, inhibiting or reducing muscle loss due to a muscle wasting disoidcr; 4) treating, preventing, inhibiting, reducing or suppressing muscle wasting due to a muscle wasting disorder; and/or 5) treating, preventing, inhibiting, reducing or suppressing muscle piotein catabolism due to a muscle wasting disoider. In one embodiment the SARM compound is a compound of foimula (T), (II), (III), oi (TV), as described herein, In another embodiment, the invention provides a composition comprising a SARM of tliis invention for use in the methods as described herein. [0076] In one embodiment, the invention provides a use of SARM compounds for treating a subject suffering from a muscle wasting disoider. In another embodiment the SARM compound is of formula (I), (II), (UT), or (IV). In another embodiment, the SARM compound is of formula (I), (II), (HI), or (IV) or its prodrug, analog, isomer, metabolite, derivative, pharmaceutically acceptable salt, pharmaceutical product, polymorph, crystal, impurity, N-oxide, hydrate oi any combination thereof, or a composition comprising the same. Thus, treating a subject suffering from a muscle wasting disordei.

[0077] In another embodiment, the use of a SARM compound for tieating a subject suffering fiom a muscle wasting disorder includes administering a pharmaceutical composition including the SARM compound. In another embodiment, the administering step includes intravenously, intraaiterially, oi intramuscularly injecting to said subject said pharmaceutical composition in liquid foim; subcutaneously implanting in said subject a pellet containing said pharmaceutical composition; oially administering to said subject said pharmaceutical composition in a liquid or solid form; oi topically applying to the skin surface of said subject said pharmaceutical composition.

[0078] A muscle is a tissue of the body mat primarily functions as a souice of powei. There are three types of muscles in the body: a) skeletal muscle -the muscle responsible foi moving extremities and external areas of the bodies; b) cardiac muscle ~ the heart muscle; and c) smooth muscle - the muscle that is in the walls of arteries and bowel [0079] A wasting condition or disoider is defined herein as a condition or disorder that is characterized, at least in part, by an abnormal, piogressive loss of body, organ or tissue mass. A wasting condition can occur as a result of a pathology such as, for example, cancer, or an infection, or it can be due to a physiologic or metabolic state, such as disuse deconditioning that can occur, foi example, due to prolonged bed rest or when a limb is immobilized, such as in a cast. A wasting condition can also be age associated. The loss of body mass that occurs during a wasting condition can be characterized by a loss of total body weight, or a loss of organ weight such as a loss of bone or muscle mass due to a decrease in tissue protein.

[0080] In one embodiment, "muscle wasting" or "muscular wasting", used herein interchangeably, refei to the piogressive loss of muscle mass and/or to the progiessive weakening and degeneration of muscles, including the skeletal or voluntary muscles which control movement, cardiac muscles which control the heart, and smooth muscles. In one embodiment, the muscle wasting condition or disorder is a chronic muscle wasting condition or disorder, "Chronic muscle wasting" is defined herein as the chronic (i,e, persisting over a long period of time) progressive loss of muscle mass and/oi to the chronic progressive weakening and degeneration of muscle.

[0081] The loss of muscle mass that occurs during muscle wasting can be characterized by a muscle protein breakdown or degradation, by muscle protein catabolism. Protein catabolism occurs because of an unusually high rate of protein degradation, an unusually low rate of protein synthesis, oi a combination of both Protein catabolism or depletion, whether caused by a high degree of protein degradation or a low degree of protein synthesis, leads to a deciease in muscle mass and to muscle wasting. The term "catabolism'* has its commonly known meaning in the ait, specifically an eneigy burning form of metabolism.

[0082] Muscle wasting can occur as a result of a pathology, disease, condition ox disorder. In one embodiment, the pathology, illness, disease or condition is chronic, hi another embodiment, the pathology, illness, disease or condition is genetic, hi another embodiment, the pathology, illness, disease or condition is neurological. In anothei embodiment, the pathology, illness, disease or condition is infectious. As described herein, the pathologies, diseases, conditions or disorders for which the compounds and compositions of the piesenl invention are administered are those that directly oi indirectly pioduce a wasting (Le, loss) of muscle mass, that is a muscle wasting disorder.

[0083] In one embodiment, muscle wasting in a subject is a result of the subject having a musculai dystrophie; muscle atrophy; X-linked spinal-bulbar musculai atrophy (SBMA), cachexia; malnutrition, tuberculosis, leprosy, diabetes, renal disease, chronic obstructive pulmonary disease (COPD), cancer, end stage renal failure, sarcopenia, emphysema, osteomalacia, oi cardiomyopathy.

[0084] In another embodiment, the muscle wasting disorder is due to infection with enterovirus, Epstein-Barr viius. heipes zoster, HIV, uypanosomes, influenze, coxsackie, rickettsia, tiichinella, schistosoma or mycobacteria.. [0085] The musculai dystrophies are genetic diseases characterized by progressive weakness and degeneration of the skeletal or voluntary muscles that control movement The muscles of the heart and some other involuntary muscles are also affected in some forms of musculai" dystrophy. The major forms of muscular dystrophy (MD) are: ducheniie muscular dystrophy, myotonic dystrophy, dυcheπne musculai- dystrophy, becker muscular dystrophy, limb-girdle muscular dystrophy, facioscapulhumeral muscular dystrophy, congenital musculai" dystrophy, oculopharyngeal muscular dystrophy, distal muscular dystrophy and emery-dreifuss muscular dystrophy.

[0086] Musculai dystrophy can affect people of all ages. Although some forms first become apparent in infancy or childhood, others may not appeal1 until middle age or later. Duchenne MD is the most common form, typically affecting children. Myotonic dystrophy is the most common of these diseases in adults,

[0087] Muscle atrophy (MA) is characterized by wasting away or diminution of muscle and a decrease in muscle mass. For example, Post-Polio MA is a muscle wasting that occurs as part of the post-polio syndrome (PPS). The ahophy includes weakness, muscle fatigue, and pain,

[0088] Another type of MA is X-linked spinal-bulbar muscular atrophy (SBMA - also known as Kennedy's Disease). This disease arises from a defect in the androgen receptor gene on the X chromosome, affects only males, and its onset is in adulthood. Because the primary disease cause is an androgen receptor mutation, androgen replacement is not a current therapeutic strategy There are some investigational studies where exogenous testosterone propionate is being given to boost the levels of androgen with hopes of overcoming androgen insensitivity and perhaps provide an anabolic effect. Still, use of supraphysiological levels of testosterone for supplementation will have limitations and other potentially serious complications.

[0089] Cachexia is weakness and a loss of weight caused by a disease or as a side effect of illness Cardiac cachexia, i.e. a muscle protein wasting of both the cardiac and skeletal muscle, is a characteristic of congestive heait failure Cancer cachexia is a syndrome that occuis in patients with solid tumors and hematological malignancies and is manifested by weight loss with massive depletion of both adipose tissue and lean muscle mass.

[0090] Cachexia is also seen in acquired immunodeficiency syndrome (AIDS), human immunodeficiency vims (HlV)-associated myopathy and/oi muscle weakness/wasting is a relatively common clinical manifestation of AIDS Individuals with HIV-associated myopathy or muscle weakness or wasting typically experience significant weight loss, generalized or proximal muscle weakness, tenderness, and muscle atrophy.

[0091] Sarcopenia is a debilitating disease that afflicts the elderly and chronically ill patients and is characterized by loss of muscle mass and function. Further, increased lean body mass is associated with decieased morbidity and mortality for certain muscle- wasting disorders. In addition, other circumstances and conditions are linked to, and can cause muscle wasting disorders For example, studies have shown that in seveie cases of chronic lowei back pain, there is paraspinal muscle wasting. [0092] Muscle wasting is also associated with advanced age. It is believed that general weakness in old age is due to muscle wasting, As the body ages, an increasing propoition of skeletal muscle is replaced by fibious tissue. The iesult is a significant reduction in muscle power, performance and endurance.

[009.3] Long term hospitalization due to illness or injury, or disuse deconditioning that occurs, for example, when a limb is immobilized, can also lead to muscle wasting. Studies have shown that in patients suffering injuries, chronic illnesses, burns, trauma or cancer, who are hospitalized for long periods of time, there is a long-lasting unilateral muscle wasting, with a consequent decrease in body mass.

[0094] Injuries or damage to the cential nervous system (CNS) are also associated with muscle wasting disorders. Injuries or damage to the CNS can be, for example, caused by diseases, trauma oi chemicals. Examples are central neive injury or damage, peripheral nerve injury or damage and spinal cord injury or damage.

[0095] In another embodiment, muscle wasting may be a result of alcoholism, and may be treated with the compounds and compositions of the invention, representing embodiments thereof,

[0096] In one embodiment, the invention provides a use of SARM compounds for preventing a muscle wasting disorder in a subject. In another embodiment the SARM compound is of formula (I), (II), (III) or (IV) In another embodiment, the SARM compound is of formula (I), (II), (III) oi (IV) or its prodrug, analog, isomer, metabolite, derivative, phaimaceutically acceptable salt, pharmaceutical product, polymoiph, crystal, impurity, N- oxide, hydrate or any combination thereof. In another embodiment, the administering comprises administering a pharmaceutical composition comprising said SARM and/or its prodrug, analog, derivative, isomei, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, or any combination thereof; and a pharmaceutically acceptable cairier. Thus, preventing a muscle wasting disorder in a subject.

[0097] In one embodiment, the invention piovides a use of SARM compounds for treating a muscle-wasting conditions associated with chronic illness. In another embodiment the SARM compound is of formula (I), (II), (IH) or (IV). In another embodiment, the SARM compound is of formula (I), (H), (IH) or1 (IV)or its prodrug, analog, isomer, metabolite, derivative, pharmaceutically acceptable salt, pharmaceutical product, polymorph, crystal, impurity, N-oxide, hydrate or any combination thereof, or a composition comprising the same. In another embodiment, the use of the SARM compounds is orally administered to said subject.

[0098] In one embodiment, the present invention provides a use of a SARM compound for preventing a muscle wasting disorder in a subject, in another embodiment, suppressing a muscle wasting disordei in a subject, in another embodiment inhibiting a muscle wasting disorder in a subject, in another embodiment reducing the incidence of a muscle wasting in a subject In another embodiment the SARM compound is of formula (I), (II), (III) or (IV). hi another embodiment, the SARM compound is of formula (I), (II), (III) oi (FV) or its prodrug, analog, isomer, metabolite, deiivatlve, pharmaceutically acceptable salt, pharmaceutical product, polymorph, crystal, impurity, N-oxide, hydrate or any combination thereof, or a composition comprising the same.

[0099] In another embodiment, this invention provides for the use of a SARM compound of this invention, or its prodrug, analog, isomer, metabolite, derivative, pharmaceutically acceptable salt, pharmaceutical product, polymorph, crystal, impurity, N-oxide, hydiate or any combination thereof, or a composition comprising the same, in treating, preventing, suppressing, inhibiting or reducing the incidence of a muscle wasting disorder in a subject,

[00100] hi anothei embodiment, this invention provides foi the use of a SARM of this invention, oi its prodrug, analog, isomer, metabolite, derivative, pharmaceutically acceptable salt, phaimaceutical product, polymorph, crystal, impurity, N-oxide, hydrate or any combination thereof, or a composition comprising the same, in increasing muscle performance, muscle size, muscle strength, or any combination thereof in a subject.

[00101] hi another embodiment, the SARMs and compositions of this invention aie useful in promoting or speeding recovery following a surgical procedure.

[00102] In one embodiment, the present invention provides a use of a SARM compound foi reducing a fat mass in a subject, hi another embodiment the SARM compound is of formula (I), (II), (III) oi (IV) hi another embodiment, the SARM compound is of foimula (I), (II), (Iu) or (N) or its prodrug, analog, isomer, metabolite, derivative;, pharmaceutically acceptable salt, pharmaceutical product, polymorph, crystal, impurity, N-oxide, hydrate or any combination thereof, or a composition comprising the same.

[00103] In another embodiment, this invention provides for the use of a SARM compound of this invention, such as one having the structure of formula (I), (II), (III) or (IY) or its prodrug, analog, isomer, metabolite, derivative, pharmaceutically acceptable salt, pharmaceutical product, polymorph, crystal, impurity, N-oxide, hydrate oi any combination thereof, or a composition comprising the same, in treating obesity or diabetes associated with a metabolic syndrome in a subject

[00104] Ln another embodiment, the subject has a hormonal imbalance, disorder, or disease. In another embodiment the subject has menopause.

[00105] In one embodiment, the present invention provides a use of a SARM compound for1 increasing a lean mass in a subject In another embodiment the SARM compound is of formula (I), (II), (111) or (IY). In another embodiment, the SARM compound is of formula (I), (II), (III) or (TV)or its prodrug, analog, isomer, metabolite, derivative, pharmaceutically acceptable salt, pharmaceutical product, polymorph, crystal, impurity, N-oxide, hydrate or any combination thereof. Thus, increasing a lean mass in a subject.

[00106] In another embodiment the subject has a hormonal imbalance, disorder, or disease. In another embodiment the subject has menopause. [00107] Figures 3-7 demonstrate that Compound III is anabolic yet minimally androgenic, thus such compounds may be useful in treating patient groups in which androgens were contraindicated in the past. Compound III was shown to stimulate muscle growth, whether in the presence or absence of testosterone while exerting anti¬ proliferative effects on the prostate, thus, in one embodiment, the SARMs of this invention restoie lost muscle mass in patients with sarcopenia oi cachexia.

[00108] In one embodiment, the SARMs of this invention are administered intravenously, via injecting the pharmaceutical composition in liquid form to the subject. In another embodiment, the SARMs of mis invention are administered intra-arterially, via injecting the pharmaceutical composition in liquid form to the subject. In another embodiment, the SARMs of this invention are administered intramuscularly via injecting the pharmaceutical composition in liquid form to the subject. In another embodiment, the SARMs of this invention are administeied stibcutaneously via implanting a pellet containing the pharmaceutical composition in the subject. In another embodiment the SARMs of this invention are administeied orally via administering the pharmaceutical composition in a liquid or solid form to the subject. In another embodiment the SARMs of this invention are administered topically via applying the pharmaceutical composition to the skin surface of the subject,

[00109] The piesent invention provides, in one embodiment, a safe and effective method for treating, preventing, suppressing, inhibiting oi reducing loss of muscle and/or muscle protein catabolism due to muscle wasting. The invention is useful, in another embodiment, in treating a subject suffering from a muscle wasting disorder, or in another embodiment in treating a bone related disorder. In one embodiment, the subject is a mammalian subject.

[00110] In another embodiment, this invention relates to a method of pi eventing, suppressing, inhibiting or reducing the incidence of obesity in a subject, comprising the step of administering to the subject a selective androgen receptor modulator (SARM) of this invention and/or its analog, derivative, isomei, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, prodrug, polymorph, crystal, or any combination thereof, in an amount effective to prevent, suppress, inhibit or reduce the incidence of obesity in the subject

[0011 Ij In one embodiment, the SARM compounds of the present invention alter the levels of leptin in a subject. In another embodiment, the SARM compounds decrease the levels of leptin. In another embodiment, the SARM compounds of the present invention increase the levels of leptin in a subject. Leptin is known to have an effect on appetite on weight loss in obese mice, and thus has been implicated in obesity.

[00112] The SARMs of this invention, in one embodiment, affect circulating, or in another embodiment, tissue levels of leptin. In one embodiment, the term clevel/s of leptin' refers to the serum level of leptin. As contemplated herein, the SARM compounds of the present invention have an effect on leptin in-vUro and in-vivo. Leptin levels can be measured by methods known to one skilled in the art, for example by commercially available ELISA kits. In addition. Leptin levels may be determined in in-vhro assays, or in in-vivo assays, by any method known to a person skilled in the art. [00113] Since leptin is implicated in controlling appetite, weight loss, food intake, and energy expenditure, modulating and/or controlling the levels of leptin is a useful therapeutic approach in treating preventing, inhibiting or reducing the incidence of obesity in subjects suffering from obesity. Modulating the level of leptin can result in a loss of appetite, a reduction of food intake, and an increase in energy expenditure in the subject, and thus may contribute to the control and treatment of obesity.

[00114] The term "obesity" is defined, in one embodiment, as an increase in body weight beyond the limitation of skeletal and physical requirement, as the result of excessive accumulation of fat in the body.

[001 15] The term "obesity-associated metabolic disorder" refers, in one embodiment, to a disorder which results from, is a consequence of, is exacerbated by or is secondary to obesity. Non-limiting examples of such a disorder are osteoarthritis, Type II diabetes mellitus, increased blood pressure, stroke, and heart disease.

[001 16] The term "osteoarthritis" refers, in another embodiment, to a non-inflammatory degenerative joint disease occurring chiefly in older people, characterized by degeneration of the articular cartilage, hypertrophy of bones and the margins and changes in the synovial membrane. Il is accompanied, in other embodiments, by pain and stiffness, particularly after prolonged activity. [00117] The term, "diabetes", in one embodiment, refers to a relative oi absolute lack of insulin leading to uncontrolled carbohydrate metabolism Most patients can be clinically classified as having either insulin-dependent diabetes mellitus (IDDM or Type-I diabetes) oi non-insulin-dependent diabetes mellitus (NIDDM or Type-II diabetes),

[00118] The term "increased blood pressiue" or "hypei tension" lefers, in other embodiments, to a repeatedly high blood pressure above 140 over 90 mrnHg. Chronically- elevated blood pressuie can cause blood vessel changes in the back of the eye, thickening of the heart muscle, kidney failure, and brain damage.

[00119] The term "stroke" refers, in other embodiments, to damage to nerve cells in the brain due to insufficient blood supply often caused by a bursting blood vessel oi a blood clot. The term "heart disease", in other embodiments, refers to a malfunction in the heart normal function and activity, including heait failure.

[00120] In addition, androgens have recently been shown to be involved in commitment of mesenchymal phiiipotent cells into myogenic lineage and to block differentiation into adipogenic lineage (Singh et al , Endocrinology, 2003, JuI 24) Accordingly, selective androgen receptor modulator compounds can be useful in methods of blocking adipogenesis, and/or alteiing stem cell differentiation, as described herein

[00121] In another embodiment this invention relates to a method of promoting, increasing or facilitating weight loss in a subject, comprising the step of administering to the subject a selective androgen receptor modulator (SARM) of this invention and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, prodrug, polymorph, crystal, or any combination thereof, in an amount effective to promote, increase or facilitate weight loss in the subject,

[00122] In another embodiment, this invention relates to a method of decreasing, suppressing, inhibiting or reducing appetite of a subject, comprising the step of administering to the subject a selective androgen receptor modulator (SARM) of this invention and/oi its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, prodrug, polymorph, crystal, or any combination thereof, in an amount effective to decrease, suppress, inhibit or reduce the appetite of the subject.

[00123] In another embodiment, this invention relates to a method of altering the body composition of a subject, comprising the step of administering to the subject a selective androgen ieceptor modulator (SARM) of this invention and/or its analog, derivative, isomei, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N- oxide, prodrug, polymorph, crystal, or any combination theieof, in an amount effective to alter the body composition of the subject, In one embodiment, altering the body composition comprises altering the lean body mass, the fat free body mass of the subject, or a combination thereof,

[00124] In another embodiment, this invention relates to a method of altering lean body mass oi fat free body mass of a subject, comprising the step of administering to the subject a selective androgen receptor modulator (SARM) of this invention and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable sail, phaπnaceutical product, hydiate, N-oxide, prodrug, polymorph, crystal, or any combination thereof, in an amount effective to alter the lean body mass or fat free body mass of the subject

[00125] In anothei embodiment, this invention ielates to a method of convening fat to ]ean muscle in a subject, comprising the step of administering to the subject a selective androgen receptor modulator (SARM) of this invention and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, phaπnaceutical product, hydrate, N- oxide, prodrug, polymorph, crystal, or any combination thereof, in an amount effective to convert fat to lean muscle in the subject.

[00126] In another embodiment, tliis invention relates to a method of treating an obesity- associated metabolic disorder in a subject, comprising the step of administering to the subject a selective androgen receptor modulator (SARM) of this invention and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, phaπnaceutical product, hydrate, N-oxide, prodrug, polymoiph, ciystal, oi any combination thereof, in an amount effective to tieat the obesity-associated metabolic disordei in the subject

[00127] Li another embodiment, this invention relates to a method of preventing, suppressing, inhibiting or reducing an obesity-associated metabolic disorder in a subject, comprising the step of administering to the subject a selective androgen ieceptor modulator (SARM) of this invention and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydiate, N-oxide3 piodrug, polymorph, crystal, or any combination thereof, in an amount effective to prevent, suppress, inhibit or reduce the obesity-associated metabolic disorder in the subject,

[00128] In one embodiment, the obesity-associated metabolic disoider is hypei tension, In another embodiment, the disorder is osteoarthritis. In another embodiment, the disoider is Type Ef diabetes mellitus, In another embodiment, the disorder is increased blood pressure In anothei embodiment, the disorder is stroke. In another embodiment, the disordei is heart disease.

[00129] In another embodiment, this invention ielates to a method of decreasing, suppressing, inhibiting or ieducing adipogenesis in a subject, comprising the step of administering to the subject a selective andiogen receptor modulator (SARM) of this invention and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, prodrug, polymorph, crystal, or any combination thereof, in an amount effective to decrease, suppress, inhibit or reduce adipogenesis in the subject.

[00130] hi another embodiment, this invention ielates to a method of altering stem cell differentiation in a subject, comprising the step of administering to the subject a selective androgen receptor modulator (SARM) of this invention and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical pioduct, hydrate, N- oxide. prodrug, polymorph, ciystal, or any combination thereof, in an amount effective to alter stem cell differentiation in the subject. [00131] In another embodiment, this invention relates to a method of altering the level of leptin in a subject, comprising the step of administering to the subject a selective andiogen receptor modulator (SARM) of this invention and/or its analog, derivative, isomei, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, prodrug, polymorph, crystal, or any combination thereof, in an amount effective to alter the level of leptin in the subject- In one embodiment, altering the level of leptin comprises decreasing the level of leptin in the subject.

[00132] In another embodiment, this invention relates to a method of decreasing, suppressing, inhibiting or reducing the level of leptin in a subject, comprising the step of administering to the subject a selective androgen receptoi modulator (SARM) of this invention and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, prodrug, polymorph, crystal, oi any combination thereof, in an amount effective to decrease, suppress, inhibit or reduce the level of leptin in the subject.

[00133] In one embodiment, the SARM that is useful in a) treating, preventing, suppressing, inhibiting, or reducing obesity; b) promoting, increasing oi facilitating weight loss; c) decreasing, suppressing, inhibiting or reducing appetite; d) altering the body composition; e) altering lean body mass or fat free body mass; f) converting fat to lean muscle; g) treating, preventing, suppressing, inhibiting, or reducing an obesity-associated metabolic disorder, for example hypertension, osteoarthritis, Type II diabetes mellitus, increased blood pressure, stroke, or heart disease; h) decreasing, suppressing, inhibiting oi reducing adipogenesis; i) altering stem cell differentiation; and/or j) alleiing the level of leptin, is a compound represented by the structure of formula (I), (II), (III) oi (IV).

[00134] In one embodiment, the SARMs of this invention find utility in treating oi halting the progression of, or treating symptoms of diabetes. In anothei embodiment, the SARMs of this invention are useful in treating co-moibidities related to diabetes These conditions include: hypertension, cerebrovascular disease, atherosclerotic coronary artery disease, macular degeneration, diabetic retinopathy (eye disease) and blindness, cataracts- systemic inflammation (chaiacterized by elevation of inflammatory markers such as eiylhrocyle sedimentation iate or C-reactive protein), birth defects, pregnancy related diabetes, pre-ecclampsia and hypertension in pregnancy, kidney disease (renal insufficiency, renal failure etc), nerve disease (diabetic neuiopathy), superficial and systemic fungal infections, congestive heart failure, gout/hyperuiicemia, obesity, hypertriglyceridemia, hypercholesterolemia, fatty livei disease (non-alcoholic steatohepatitis, or NASH), and diabetes-related skin diseases such as Necrobiosis Lipoidica Diabeticorum (NLD), Blisters of diabetes (Bullosis Diabeticorum), Eruptive Xanthomatosis, Digital Sclerosis, Disseminated Granuloma Annulare, and Acanthosis Nigricans,

[00135] In one embodiment this invention provides a method for a) treating, preventing, suppressing inhibiting atherosclerosis b) treating, preventing, suppressing inhibiting livei damage due to fat deposits comprising the step of administering to the subject a selective androgen receptor modulator (SARM) of this invention and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N- oxide, prodrug, polymorph, crystal, or any combination thereof, or a composition comprising the same, in an amount effective to treat, prevent or inhibit atheroscleiosis and liver damage due to fat deposit,

[00136] In one embodiment, the SARM that is useful in a) treating, preventing, suppressing, inhibiting, or reducing atherosclerosis; b) treating, preventing, suppressing inhibiting liver damage due to fat deposits,

[00137] In one embodiment atheioscleiosis nrefers to a slow, complex disease that may begin with damage to the innermost layer of the artery. In another embodiment the causes of damage to the arterial wall may include a) elevated levels of cholesterol and in the blood; b) high blood pressure; c) tobacco smoke d) diabetes. In another embodiment, the condition is treatable in a smoker, despite the fact that tobacco smoke may gieatly worsen atheroscleiosis and speed its growth in the coronary arteries, the aoita and arteries in the legs. Similarly, in another embodiment, the methods of this invention may be useful in ti eating subjects with a family history of premature cardiovasculai disease who have an increased risk of atherosclerosis.

[00138] In one embodiment, liver damage due to fat deposits refer to the build-up of fat in the liver cells forming a Fatty Liver which may be associated with or may lead to inflammation of the liver. This can cause scarring and hardening of the liver. When scarring becomes extensive, it is called cirrhosis, In another embodiment the fat accumulates in the liver as obesity. In another embodiment fatty liver is also associated with diabetes mellirus, high blood triglycerides, and the heavy use of alcohol. In another embodiment fatty Liver may occur with certain illnesses such as tuberculosis and malnutrition, intestinal bypass surgery for obesity, excess vitamin A in the body, or the use of certain drugs such as valproic acid (trade names: Depakene/Depakote) and corticosteroids (cortisone, prednisone). Sometimes fatty liver occurs as a complication of pregnancy

[00139] In one embodiment, the methods of use in treating a subject aie where the subject is a human, and in another embodiment, where the subject is male, or in another embodiment, where the subject is female

[00140] In another embodiment, this invention provides for the use of a SARM of this invention, or a composition comprising the same, in promoting or suppressing spermatogenesis in a male subject. Some of the SARMs of the piesent invention exhibit, inter-aϊia, andiogenic activity, which in turn stimulates spermatogenesis. In other embodiments, the SARMs of this invention exhibit antagonist activity in the gonads of a subject, which in turn, may suppress speimatogenesis, In one embodiment, the SARMs may therefore be used as a contraceptive.

[00141] It is to be understood that any use of the SARMs of this invention, including, inter-alia, uses in applications regarding diseases or conditions which pertain to muscle, fat, cardiac, liver, gonadal or bone tissue, whereby administration of the SARM compounds of this invention, or a composition comprising the same, alter the course of such diseases or conditions favorably for a subject, are to be considered as part of this invention. [00142] The following examples are presented in order to more fully illustiate the prefeired embodiments of the invention- They should in no way, howevei, be construed as limiting the broad scope of the invention.

EXAMPLES EXAMPLE 1: Effects of Selective Androgen Receptor Modulator (SARM) compound IH on Progenitor Cell Differentiation To Osteoblasts and Osteoclasts.

Materials and Methods: Chemicals [00143] Compound III, THT and PTH were prepared at concentrations ianging fiom InM-I μM. Animals [00144] Four month old female rats were sacrificed by euthanasia and the femurs were excised from the animals The femurs weie cleaned off any muscle and connective tissues and were stored on ice in Minimum Essential Medium (MEM) with penicillin, Streptomycin and Fungizone until the cells were cultuied.

Bone Marrow Cell Culture [00145] All cell culture materials were obtained from Invitrogen (Carlsbad, CA), The femurs were first rinsed in 70% ethanol and were washed three times with 5 ml each of penicillin and streptomycin. Both the ends of the femurs were snapped and the bone marrow cells were flushed with 15 ml of MEM with penicillin, Stteptoraycin and Fungizone into a 50 ml conical tube and stored on ice. The same procediue was performed with all the femurs. The bone marrow cells and were pooled were centrifuged at 1000 ipm for 5 min in a clinical centrifuge, The cells were resuspended in MEM without phenol ied supplemented with 10% charcoal stiipped serum, penicillin, streptomycin and fungizone The cells were tiituiated lhiough a 22g needle, counted undei micioscope and weie plated at 1 5 million cells per well of a 6 well plate in MEM without phenol red supplemented with 15% charcoal stripped serum, penicillin streptomycin, 300 ng/ml fungizone, 0,28 niM Ascorbic acid and 10 niM β-glycerophosphate to diffeieπtiate towards fibroblast/osteoblast lineage and at 2.5 million cells per well of a 24 well piate in MEM without phenol red supplemented with 10% chaicoal stiipped serum, penicillin streptomycin and 300 ng/ml fungizone to differentiate towards osteoclast lineage The medium was changed on day 2 and the cells were treated with the indicated hormone. Osteoclast cultures weie can ied out in the presence of 50 ng RANK Ligand and 10 ng GM-CSF to induce osteoclastogenesis. Medium was completely changed every thiid day for osteoclast cullυies Foi fibroblast cultures, half the cultuie medium was changed every third day to leave the growth factors secreted by the cells.

Staining of Cells [00146] At the end of 12 days, the cells were fixed in 10% buffered foimalin for fibroblast cultuied and in 4% formaldehyde in PBS for osteoclast cultures. The fibroblasts weie stained for alkaline phosphatase activity and the CD. at 405 ran was measured using a spectrophotometer as described earlier. Osteoclasis were stained for Tartarate Resistant Acid Phosphatase Activity (TRAP) and cells having 2 or more nuclei were counted under the micioscope and plotted as indicated earlier. Results

SARMs are potent inducers of differentiation of bone marrow cells towards the ■ osteoblast and osteoclast lineage

[00147] Androgens exeit anabolic effects on bone and lack of androgens under conditions such as androgen deprivation therapy in prostate cancer and in old age have clearly indicated the benefits of androgens as a bone protective hormone. Howevei, the use of ectopic androgen is limiied due to its side effects and also due to the risk of conversion of androgens to estrogens.

[00148] In order to determine whether a SARM could be therapeutic yet obviate the above side-effects, various selective androgen receptoi modulators (SARMs) weie evaluated in terms of their ability to have bone protective effects, with fewer side effects, as seen with the parent hormone. The efficacy of Di-hydro testosterone (DHT) and Parathyroid hormone (PTH) were compared to a SARM, Compound III in teims of their ability to differentiate primary rat bone marrow cells towards the osteoblast and the osteoclast lineage (Figures 1 and 2). Bone maπow cells from rats were cultured in the presence or absence of the above indicated hormones for 12 days in culture medium and were evaluated in terms of their differentiation towards osteoblast or osteoclast lineage. [00149] DHT and Compound III all increased differentiation of primary bone marrow cells towaid the osteoblast lineage as measured by alkaline phosphatase (ALP) activity of the cells (Fig. 1 ). At 1 μM concentration, DHT and the SARM induced the ALP activity comparably whereas at lowei concentrations of 100 nM and 10 nM Compound III showed better induction than the DHT. PTH5 another bone anabolic hormone induced the ALP staining only at higher concenlialion but not at lower concentrations.

[00150] Fig. 2 shows a clear increase in the number of TRAP positive multinucleated osteoclasts, when cells weie incubated in the presence of RANK ligand and GM-CSF Treatment of cells with DHT or SARM significantly inhibited RANK ligand and GM- CSF- induced TRAP positive multinucleated osteoclast proliferation. PTH inhibited induction at higher concentrations, howevei, at lower concentrations, PTH increased the nurnbei of TRAP positive osteoclasts. Estradiol inhibited osleoclastogenesis, at ail dosages evaluated.

EXAMPLE 2: SARM BONE EFFECTS ALONE AND IN COMBINATION WITH THE ANTI- RESORPTIVE AGENT, ALENDRONATE

Materials and Methods: [00151] Sixty female, virgin, intact Sprague-Dawley rats were obtained from Charles River Laboratories (Wilmington, MA) and aged to 23 wks. The animals weie housed 2-3 per cage and acclimated to a 12-h light/dark cycle. Food (7012C LM-485 Mouse/Rat Sterilizable Diet, Harlan Teklad, Madison, WI) and water were provided ad libitum The Institutional Animal Care and Use Committee of the University of Tennessee reviewed and approved the animal protocol for this study. [00152] Sham surgeries or ovariectomies were performed on Day 0, The study was cornpiised of six treatment groups as follows: (1 ) intact + vehicle, (2) intact + COMPOUND 111, (3) OVX + vehicle, (4) OVX + COMPOUND III, (5) OVX + alendronate (6) OVX + alendronate + COMPOUND ITL Doses (200 L) were administeied daily via oral gavage in a vehicle of DMSO:PEG300 (10:90) beginning on Day 1 , Animals weie sacrificed on Day 45 of the study. Femurs were lemoved, cleared of soft tissue, and stored in saline soaked gauze at -200C until analysis. Nine animals died during the course of the study. These deaths were attributed to surgical complications arising from the ovariectomies and technical errors during oral dosing (i.e., dosing solution delivered into the lungs) Dose groups are listed in Table 1. Group Gonadal Status Treatment Dose Animals/group 1 Intact Vehicle N/A 9 2 Intact COMPOUND III 3 mg/day 9 3 OVX Vehicle N/A 7 4 OVX COMPOUND III 3 mg/day 8 5 OVX Alendronate 1 mg/day 10 Alendionate + 1 mg/day + 3 6 OVX COMPOUND IH mg/day 8 Table 1. Treatment groups

[00153] The left femurs were sent to SkeleTech Inc (Bothell, WA) for biomechanical strength (three point bending) and pQCT analysis A Stratec XCT RM and associated software (Stratec Medizintechnik GmbH, Pforzheim, Germany. Software version 5.40 C) were used for the pQCT analysis. The femur was analyzed at both the mid-shaft and distal regions. The mid-shaft analysis was performed on the region at 50% of the length of the femur. The distal analysis was performed on the region at 20% of the length of the femur starting at the distal end. One 0,5 mm slice perpendicular to the long axis of the femur was used for analysis. Total bone mineral content, total bone area, total bone mineral density, cortical bone mineral content, cortical bone area, cortical bone mineral density, cortical thickness, periosteal perimeter (circumference) and endosteal perimeter were determined at the mid-shaft of the femur. At the distal femur, total bone mineral content, total bone area, total bone mineral density, trabecular bone mineral content, trabecular bone area and trabecular bone mineral density were determined. Following pQCT analysis, the femoral strength was determined by a three-point bending test. The anterior to posterior diameter (APD) (unit:mm) at the midpoint of the femoral shaft was measured with an electronic caliper. The femur was placed on the lower supports of a three-point bending fixture with the anterior side of the femur facing downward in an lnslron Mechanical Testing Machine (Instron 4465 retrofitted to 5500)(Canton, MA). The length (L) between the lower supports was set to 14 mm. The upper loading device was aligned to the center of the femoral shaft. The load was applied at a constant displacement rate of 6 mm/min until the femur broke. The mechanical testing machine directly measured the maximum load (Fu) (unit:N), stiffness (S) (units:N/mm), and energy absorbed (W) (unifcmJ), The axial area moment of inertia (I) (unit:mm'1) was calculated by the software during the pQCT analysis of the femoral mid-shaft. Stress ( ) (units:N/mm2), elastic modulus (E) (unit:Mpa), and toughness (T) (units:mJ/rn3) were calculated by the following formulas: stress: = (Fu * L *(a/2)) / (4* I); elastic modulus: E = S*L3/(48*I); and toughness: T = 3*W*(APD/2)2/(L*I). Statistical analysis was performed by Student's T-test. P-values of less than 0.05 were considered as statistically significant diffeiences. Results: [00154] Femoral maximum load was determined by 3-point bending of the femur. Results aie shown in Figure 3. No differences were observed between the intact vehicle (210 N) and the OVX vehicle (212 N) control groups. We obseived trends in the COMPOUND III treated groups with maximum load increasing to 224 and 233 newtons in the intact and OVX groups, respectively The alendronate (213 N) and alendronate + COMPOUND III (207N) gioups were not different from contiols,

[00155] Trabecular bone mineial density was analyzed by pQCT at the distal femur. Results are shown in Figure 4. We observed significant tiabecular bone loss following OVX. Trabecular bone density decreased from 379 to 215 mg/mm3 in the intact and OVX vehicle control groups, respectively. In intact animals tieated with COMPOUND III, we observed a slight inciease in trabecular bone density to 398 mg/mm3 In OVX animals treated with COMPOUND III, we observed a significant increase over the OVX vehicle control group to 406 mg/mm3. Alendronate incieased trabecular bone density to 480 mg/mm3. The combination therapy of Alendronate and COMPOUND III showed additive effects increasing trabecular bone density to 552 mg/mm3.

EXAMPLE 3: Androgenic & Anabolic Activity in Intact and ORX Rats Materials and Methods; [00156] Male Sprague-Dawley rats weighing approximately 20Og were purchased from Hailan Byproducts for Science (Indianapolis, IN). The animals were maintained on a 12- h light/dark cycle with food (7012C LM-485 Mouse/Rat Sterilizable Diet, I-Iailan Teklad, Madison, WI) and water available ad libitum. The animal protocol was reviewed and appioved by the Institutional Animal Care and Use Committee of the University of Tennessee Anabolic and androgenic activity of Compound III in intact animals was evaluated, and the dose response in acutely orchidectomized (ORX) animals was evaluated as well Regenerative effects of Compound III in chronically (9 days) ORX iats was also assessed. [00157] The compound was weighed and dissolved in 10% DMSO (Fisher) diluted with PEG 300 (Acros Organics, NJ) for preparation of the appropiiate dosage concenliations. The animals were housed in groups of 2 to 3 animals per cage Intact and ORX animals were randomly assigned to one of seven groups consisting of 4 to 5 animals per group. Control groups (intact and ORX) were administered vehicle daily. Compound HI was administered via oral gavage at doses of 0,01, 0.03, 0.1, 0.3, 0 75, and 1 mg/day to both intact and ORX groups [00158] Castrated animals (on day one of the study) were iandomly assigned to dose groups (4-5 animals/group) of 0.01, 0.03, OJ , 0,3, 0.75, and 1 mg/day, foi dose-response evaluation. Dosing began nine days post ORX and was administered daily via oral gavage for fouiteen days. The animals were sacrificed under anesthesia (Icetamine/xyalzine, 87:13 mg/kg) after a 14-day dosing regimen, and body weights were recorded, In addition, ventral prostate, seminal vesicles, and levator ani muscle were removed, individually weighed, normalized to body weight, and expressed as a percentage of intact control. Student's T-test was used to compare individual dose groups to the intact control group. Significance was defined a priori as a P-value < 0.05 As a measure of androgenic activity, ventral prostate and seminal vesicle weights weie evaluated, whereas levator ani muscle weight was evaluated as a measure of anabolic activity- Blood was collected from the abdominal aorta, centrifuged, and sera were frozen at -8O0C prior to determination of serum hoimone levels. Seium luetinizing hormone (LH) and follicle stimulating hormone (FSH) concentrations were determined by the University of Virginia Center for Reseaich in Reproduction Ligand Assay and Analysis Core (NICHD (SCCPRR) Grant U54-HD28934).

Results:

[00159] Prostate weights following Compound III treatment were 11 1% ± 21%, 88% ± 15%, 77% ± 17%, 71% ± 16%, 71% ± 10%, and 87% ± 13% of intact controls following doses of 0.01 , 0,03, 0.1, 03, 0.75, and 1 mg/day, respectively (Figure 5). Similaily, seminal vesicle weights decreased to 94% ± 9%, 77% ± 11%, 80% ± 9%, 73% ± 12%, 77% ± 10%, and 88% ± 14% of intact controls following doses of 0.01, 0.03, 0,1, 03, 0,75, and 1 mg/day, respectively Significant increases weie seen in levator ani muscle weights of sham animals, however, in all dose groups, when compared to intact controls. The levator ani muscle weights were 120% ± 12%, 116% ± 7%, 128% ± 7%, 134% ± 7%, 125% ± 9%, and 146% ± 17% of intact controls coπesponding to 0,01, 0,03, 0.1, 03, 0.75, and 1 ,0 mg/day dose groups, respectively. The results are presented graphically in Figure 5. [00160] Compound III partially maintained prostate weight following orchidectomy Prostate weight in vehicle treated ORX controls decreased to 5% ± 1% of intact controls. At doses of 0.01 , 0.03, 0,1, OJ, 0.75, and LO mg/day, Compound III maintained prostate weights at 8% ± 2%, 20% ± 5%, 51% ± 19%, 56% ± 9%, 80% ± 28%, and 74 ± 12.5% of intact controls, respectively. In castrated controls, seminal vesicle weight decreased to 13% ± 2% of intact controls. Compound III partially maintained seminal vesicle weights in ORX animals. Seminal vesicle weights from drug treated animals were 12% ± 4%, 17% ± 5%, 35% ± 10%, 61% ± 15%, 70% ± 14%, and 80% ± 6% of intact contiols, following doses of 0.01, 0.03, 0.1 , 0.3, 0.75, and 1.0 mg/day, lespeclively. In ORX contiols the levator and muscle weight decreased to 55% ± 7% of intact controls. We observed an anabolic effect in the levator ani muscle of Compound III treated animals Compound III fully maintained levaor ani muscle weights at doses > 0.1 mg/day. Doses > 0 1 mg/day resulted in significant increases in levator ani weight compared to that observed in intact controls. Levator ani muscle weights as a percentage of intact controls were 59% ± 6%, 85% ± 9%, 112% ± 10%, 122% ± 16%, 127 ± 12%, and 129.66 ± 2% for the 0.01, 0,03, 0.1, 0,3, 0.75, and 1.0 mg/day dose groups, respectively. Results are graphically presented in Figure 6. En^ and ED50 values were determined in each tissue by nonlinear regression analysis in WinNonlin© and presented in Figure 7 E,,,1LS values were 83% ± 25%, 85% ± 1 1%, and 131% ± 2% for prostate, seminal vesicles, and levator ani, respectively. The ED50 in prostate, seminal vesicles, and levator ani was 0.09 ± 0.07, 0.17 ± 0.05, and 0.02 ± 0 01 mg/day, respectively.

Scrum Hormone Analysis [00161] Serum LH and FSI-I data for the animals are presented in Table 1. LH decreased in a dose-dependent manner in both intact and castiated animals. Following doses > 0.1 mg/day, LH levels were below the limit of quantitation (0.07 ng/mL). The 0,1 mg/day dose in ORX animals returned LH levels back to those seen in intact controls. Similar effects were observed with FSH. In intact animals, a significant decrease in FSH levels was observed with the 0,75 and 1 mg/day doses. In ORX animals, a dose- dependent decrease in FSH levels was observed. Doses of Compound III > 0.1 mg/day in ORX animals ietumed FSH levels to those of intact controls,

Table I Serum LH and FSH levels From animals in Arm ! and Arm2, "P<0 05 vs Intact Controls, bP<0,05 vs ORX Controls

Androgenic & Anabolic Activity Following Delayed Dosing [00162] Compound III partially restored both prostate and seminal vesicle weight in ORX animals. Prostates were restored to 9% ± 3%, 11% ± 3%, 23% ± 5%, 50% db 13%, 62% ± 12%, and 71% ± 5%, while seminal vesicles were iestorcd 7% ± 1%, 9% ± 1%, 23% ± 8%, 49% ± 5%, 67% ± 12%, and 67% ± 11% of intact controls for the 0.01, 0.03, 0.1, 0.3, 0.75, and 1.0 mg/day dose groups, respectively. Compound III fully restored levator ani muscle weight at doses > 0.1 mg/day, Levatoi ani muscle weights weie restored to 56% ± 7%, 82% ± 9%, 103% ± 11 %, 113% ± 1 1 %, 121 % ± 7%, and 120% ± 7% corresponding to doses of 0.01, 0.03, 0 1, 0,3, 0.75, and 1.0 mg/day, respectively. Results are presented graphically in Figure 8. Emax and ED50 values were determined in each tissue by nonlinear 1 egression analysis in WinNonlin® and presented in Figure 9. Emax values were 75% ± 8%, 73% ± 3%, and 126% ± 4% for prostate, seminal vesicles, and levatoi ani, respectively. The ED50 in prostate, seminal vesicles, and levator ani was 0.22 ± 0.05, 0.21 ± 0.02, and 0 013 ± 0 01 mg/day, respectively.

EXAMPLE 4: Pharmacokinetic characterization of the novel oral anabolic SARM compound HI; The first analysis in healthy male volunteers

Materials and Methods [00163] Cohorts of a maximum of 12 healthy male volunteers were dosed at each dose level (9 active, 3 placebo) in a randomized, double-blind study design. Eight cohorts were recruited (aged 18-45 years) and each cohort received one single oral dose corresponding to either 1, 3, 10, 30 or 100 mg compound HI (or placebo of equal volume of PEG300) in solution, or 3 or 30 mg in experimental capsules The effect of raicronization (i.e. particle size reduction) was investigated on the phaimacokineties of compound III in the 30 mg solid oral dosage form. Samples for pharmacokinetic assessment of parent drug were taken for up to 72 horns following dosing.

Results [00164] Doses of compound HI in PBG300-based solutions at 1, 3, 10, 30 and 100 mg were rapidly absorbed from the gastrointestinal tract. All dose levels resulted in plasma compound III concentrations that weie quantifiable through the last time point collected (72 hours) (Figure 10 -12). Exposure (Cmax and AUC) to compound III increased with increasing dose and was linear foi solutions over the dose range 1 to 100 mg. Tmax was achieved between 0.8 and 2.3 hours (median value = 1.0 houis) for compound III in solution, and between 3 2 and 3.9 hours following the solid oral formulations (Figure 13 & 14). The terminal elimination half-life ranged from 19 to 22 hours (median value = 20 hours) for 1-100 mg solutions and the 3 mg capsule, and was increased with the 30 mg capsules to 27 and 31 hours for micronized and non- micronized, although not significantly (p>0.1 ). Oral cleaiance was inversely associated with half-life, with the 30 mg non-micronized capsule exhibiting the longest half-life and the lowest clearance compared to the othei dosage forms and amounts. The 3 mg non-micronized capsule and solution were equally bioavailable, but at the higher dose (30 mg) micronizaϋon improved oral bioavailability (p<0.05) (Figuie 12). As suggested by a consistent second peak over the elimination phase of the drug, it is possible mat enterohepatic recirculation through the hepatobiliary system plays a role in redistribution of parent diug. EXAMPLE 5 ANABOLIC AND ANDROGENIC ACTIVITY OF SARMs [00165] Materials. The SARMs are synthesized essentially in accordance with methods as described in United States Patent Application Publication Number 2004/0014975 AL Alzet osmotic pumps (model 2002) are purchased from Alza Corp.. (Palo Alto, CA).

[00166] The SARMs tested will comprise the following:

And

And their activity will be compared to that of :

[0Ol 67] Study Design Immature male Spragiie-Dawley rats, weighing 90 to 10Og, are randomly distributed into groups, with at least 5 animals per group. One day prior to the start of drug treatment, animals are individually removed fiom the cage, weighed and anesthetized with an intiaperitoneal dose of ketamine/xylazine (87/13 mg/kg; approximately 1 mL per kg). When appropriately anesthetized (Le,, no response to toe pinch), the animals' ears are marked for identification purposes. Animals are then placed on a sterile pad and their abdomen and scrotum washed with betadine and 70% alcohol The testes are removed via a midline sciotal incision, with sterile suture being used to ligate supra-testicular tissue prioi to surgical lemoval of each testis. The surgical wound site is closed with sterile stainless steel wound clips, and the site cleaned with betadine. The animals are allowed to recovei on a sterile pad (until able to stand) and then returned to their cage.

[00168] Twenty-four hours later, animals are re-anesthetized with ketamine/xylazine, and an Alzet osmotic pump(s) (model 2002) containing the SARM compound is placed subcutaneouly in the scapulai region. Osmotic pumps contain the appropriate 12 treatment (as described in Example 3) dissolved in polyethylene glycol 300 (PEG300). Osmotic pumps are filled with the appropriate solution one day prior to implantation Animals are monitored daily for signs of acute toxicity to drug treatment (e.g., lethargy, rough coat).

[00169] After 14 days of drug treatment, rats are anesthetized with lcetamine/xylazine Animals are sacrificed by exsanguination under anesthesia. A blood sample is collected by venipuncture of the abdominal aoi ta, and submitted for complete blood cell analysis. A poition of the blood is placed in a separate tube, centrifuged at 12.00Og for 1 minute, and the plasma layer removed and frozen at - 200C. The ventral prostates, seminal vesicles, levatoi ani muscle, liver, kidneys, spleen, lungs, and heart are removed, cleared of extianeous tissue, weighed, and placed in vials containing 10% neutral buffered foimalin Preseived tissues are subjected to histopathological analysis,

[00170] For data analysis, the weights of all organs are normalized to body weight, and analyzed for any statistical significant difference by single-factor ANOVA. The weights of prostate and seminal vesicle are used as indexes for evaluation of androgenic activity, and the levator ani muscle weight is used to evaluate the anabolic activity.

[00171] Testosterone propionate (TP), at inci easing doses, is used as the positive control of anabolic and androgenic effects. Effects of particular compounds may thus be compared to that of TP. [00172] The weights of prostate, seminal vesicle, and levator ani muscle in castrated, vehicle-tieated rats are expected to decrease significantly, due to the ablation of endogenous androgen production. Exogenous administration of testosterone propionate, an androgenic and anabolic steroid, are expected to increase the weights of prostate, seminal vesicle, and levator ani muscle in castrated iats in a dose-dependent manner. The SARMs will be compaiatively evaluated for their effect on the weights of prostate, seminal vesicle, and levator ani muscle in castrated animals. Compounds which show lower potency and intrinsic activity in increasing the weights of prostate and seminal vesicle, but a greater potency and intrinsic activity in incieasing the weight of levator ani muscle, will be considered to be poorly andiogenic yet anabolic, and represent compounds which would be useful in therapy of, for example, prostate cancer, or fot treating side effects associated with current therapies for prostate cancer, such as, for example, androgen deprivation theiapy. 173]

EXAMPLE 6

SARM REDUCTION OF CHOLESTEROL LEVELS Materials and Methods

[00174] One hundred Spiague Dawley rats (50 male and 50 female) were divided into five groups (n=10 per gender per group), representing vehicle only (PEG300:40% Cavasol© [75/25 (v/v)]), and four dose groups of Compound III. Animals were administered Compound III once daily by oial gavage according to their most recent body weight with doses of either 0, 3, 10, 30 or 100 mg/kg. During the study period, rats had access to water and a standard laboiatoiy diet of Plarlan Taldad Rodent Chow ad libitum. After 28 consecutive days of dosing, animals were fasted overnight, blood samples were collected and processed to yield serum. Serum levels of total cholesterol were determined using an automated laboiatory assay method. Results

[00175] The male and female rats in the vehicle only group (0 mg/kg) had serum total cholesteiol values of 92±13.5 and 102±13 mg/dL respectively These values are considered within the noimal historical range for the testing laboratory. Daily oral doses of Compound III at oi above 3 mg/lcg caused a significant reduction in total cholesterol levels in both male and female rats. At 3 mg/kg, compared to vehicle control animals, an approximate 30% reduction in total cholesterol was noted where males and females had 63±17.4 and 74±14.2 mg/dL respectively. Although a slightly greater effect was noted at the highest dose gioup (100 mg/kg per day), in geneial, a dose-response relationship was not observed in the reduction of total cholesteiol levels in the Sprague Dawley rat. Results are presented graphically in Figure 15.

[00176] The effect of SARMs in causing acute toxicity, as gauged by diagnostic hematology tests and visual examination of animals receiving treatments will be assessed, as will suppression of luteinizing hormone (LH) or follicle stimulating hormone (FSH), as described in Example 4 hereinabove. [00177] Wliile certain features of the invention have been illustrated and described herein, many modifications, substitutions, changes, and equivalents will now occur to those of ordinaiy skill in the art. It is, therefore, to be understood that the appended claims are intended to cover all such modifications and changes as fall within the true spirit of the invention.