CELL PERMEABLE CYCLIC PEPTIDE SCAFFOLDS

CROSS-REFERENCE TO RELATED APPLICATION

Pursuant to 35 U.S.C. § 119(e), this application claims priority to the filing date of United States Provisional Patent Application Serial No. 62/489,337 filed on April 24, 2017, the disclosure of which application is incorporated herein by reference.

INTRODUCTION

Certain undruggable targets lack well defined binding pockets. Inhibitors of these undruggable targets may be larger and more complex than typical small molecule

drugs. The targets of existing small molecule drugs make up only a small fraction of the protein encoding genome, and it is estimated that the total "druggable" genome (accessible to inhibition by classic small molecules) represents a small fraction of the total number of potential targets. The number of therapeutic targets that have been unexploited due to poor druggability, such as transcription factors and non-coding RNAs, therefore represent a vast opportunity to make therapeutic advances in virtually every disease category.

Macrocylic compounds, such as cyclic peptides exhibit therapeutic potential due to protein-protein interactions (PPIs). Cyclization can often improve potency in peptides as well as proteolytic stability. In addition, the synthesis of cyclic peptides is much more modular and straightforward than the synthesis of organic molecules of similar size and complexity. Large combinatorial libraries of cyclic peptides, derived from methods such as DNA-encoded synthesis, phage display and mRNA-display, have yielded potent inhibitors against a variety of undruggable or challenging targets, such as XIAP10 and E6AP11. SUMMARY

The present disclosure provides cell permeable cyclic peptide scaffolds, pharmaceutical compositions, and their methods of use, where the cell permeable cyclic peptide scaffolds include a hexapeptide composed of naturally or non-naturally occurring amino acids. In embodiments, the cyclic peptide scaffold is a compound of Formula I:

Cyclo [Z-Y-X-Pro-Y-Phe] Formula I

wherein:

Pro is L-proline or D-proline;

Phe is L-phenylalanine or D-phenylalanine;

each Ri is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl, or optionally, R ¹ together with the atoms to which it is bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring;

each R ₂ is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl, or optionally, R ¹ together with the atoms to which it is bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring;

each R ₃ is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl, or optionally, R ¹ together with the atoms to which it is bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring;

A is selected from -NR _a -, -O- or -S-;

B is selected from -NR _t ,-, -O- or -S-;

C is selected from -NR _C -, -O- or -S-;

each R _a , R _b , R _c is independently selected from hydrogen, alkyl, substituted alkyl, aryl and substituted aryl, or

Ri and R _a together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring; R2 and ¾ together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring;

R3 and R _c together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring;

n is an integer from one to 5 and a is an integer from one to 5;

p is an integer from one to 5 and b is an integer from one to 5; and

r is an integer from one to 5 and c is an integer from one to 5 ;

or a pharmaceutical acceptable salt, solvate or hydrate thereof.

Compositions containing one or more of the subject cell permeable cyclic peptide scaffolds are also provided. In some embodiments, compositions include one or more of the cell permeable cyclic peptide scaffolds described herein, or pharmaceutically acceptable salt, solvate or hydrate thereof and a pharmaceutically acceptable vehicle. Dose units containing one or more of the subject compositions are also provided. A library having a plurality of the cell permeable cyclic peptide scaffolds are also described. For example, the library may include 50 or more of the subject cyclic peptides, each cyclic peptide independently being a compound of Formula I.

DEFINITION OF CERTAIN CHEMICAL TERMINOLOGY

The following terms have the following meaning unless otherwise indicated. Any undefined terms have their art recognized meanings.

As used herein, the term "alkyl" by itself or as part of another substituent refers to a saturated branched or straight-chain monovalent hydrocarbon radical derived by the removal of one hydrogen atom from a single carbon atom of a parent alkane. Typical alkyl groups include, but are not limited to, methyl; ethyl, propyls such as propan-l-yl or propan-2-yl; and butyls such as butan-l-yl, butan-2-yl, 2-methyl -propan-l-yl or 2-methyl-propan-2-yl. In some embodiments, an alkyl group comprises from 1 to 20 carbon atoms. In other embodiments, an alkyl group comprises from 1 to 10 carbon atoms. In still other embodiments, an alkyl group comprises from 1 to 6 carbon atoms, such as from 1 to 4 carbon atoms.

"Alkanyl" by itself or as part of another substituent refers to a saturated branched, straight-chain or cyclic alkyl radical derived by the removal of one hydrogen atom from a single carbon atom of an alkane. Typical alkanyl groups include, but are not limited to, methanyl; ethanyl; propanyls such as propan-l-yl, propan-2-yl (isopropyl), cyclopropan-l-yl, etc.; butanyls such as butan-l-yl, butan-2-yl (sec-butyl), 2-methyl-propan-l-yl (isobutyl), 2-methyl-propan-2- yl (t-butyl), cyclobutan-l-yl, etc.; and the like.

"Alkylene" refers to a branched or unbranched saturated hydrocarbon chain, usually having from 1 to 40 carbon atoms, more usually 1 to 10 carbon atoms and even more usually 1 to 6 carbon atoms. This term is exemplified by groups such as methylene (-CH ₂ -), ethylene (-CH ₂ CH ₂ -), the propylene isomers (e.g., -CH ₂ CH ₂ CH ₂ - and -CH(CH ₃ )CH ₂ -) and the like.

"Alkenyl" by itself or as part of another substituent refers to an unsaturated branched, straight-chain or cyclic alkyl radical having at least one carbon-carbon double bond derived by the removal of one hydrogen atom from a single carbon atom of an alkene. The group may be in either the cis or trans conformation about the double bond(s). Typical alkenyl groups include, but are not limited to, ethenyl; propenyls such as prop-l-en-l-yl, prop-l-en-2-yl, prop-2-en-l-yl (allyl), prop-2-en-2-yl, cycloprop-l-en-l-yl; cycloprop-2-en-l-yl; butenyls such as but-l-en-1- yl, but-l-en-2-yl, 2-methyl-prop-l-en-l-yl, but-2-en-l-yl, but-2-en-l-yl, but-2-en-2-yl, buta-1,3- dien-l-yl, buta-l,3-dien-2-yl, cyclobut-l-en-l-yl, cyclobut-l-en-3-yl, cyclobuta-l,3-dien-l-yl, etc.; and the like.

"Alkynyl" by itself or as part of another substituent refers to an unsaturated branched, straight-chain or cyclic alkyl radical having at least one carbon-carbon triple bond derived by the removal of one hydrogen atom from a single carbon atom of an alkyne. Typical alkynyl groups include, but are not limited to, ethynyl; propynyls such as prop-l-yn-l-yl, prop-2-yn-l-yl, etc.; butynyls such as but-l-yn-l-yl, but-l-yn-3-yl, but-3-yn-l-yl, etc.; and the like.

"Acyl" by itself or as part of another substituent refers to a radical -C(0)R 30 , where R 30 is hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl as defined herein and substituted versions thereof. Representative examples include, but are not limited to formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl, benzylcarbonyl, piperonyl, succinyl, and malonyl, and the like.

The term "aminoacyl" refers to the group -C(0)NR ²¹ R ²² , wherein R ²¹ and R ²² independently are selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R ²¹ and R ²² are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

"Alkoxy" by itself or as part of another substituent refers to a radical -OR ³¹ where R ³¹ represents an alkyl or cycloalkyl group as defined herein. Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclohexyloxy and the like.

"Alkoxycarbonyl" by itself or as part of another substituent refers to a radical -C(0)OR ³¹ where R ³¹ represents an alkyl or cycloalkyl group as defined herein. Representative examples include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,

butoxycarbonyl, cyclohexyloxycarbonyl and the like.

"Aryl" by itself or as part of another substituent refers to a monovalent aromatic hydrocarbon radical derived by the removal of one hydrogen atom from a single carbon atom of an aromatic ring system. Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, trinaphthalene and the like. In certain embodiments, an aryl group comprises from 6 to 20 carbon atoms. In certain embodiments, an aryl group comprises from 6 to 12 carbon atoms. Examples of an aryl group are phenyl and naphthyl.

"Arylalkyl" by itself or as part of another substituent refers to an acyclic alkyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp ³ carbon atom, is replaced with an aryl group. Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenylethan-l-yl, 2-phenylethen-l-yl, naphthylmethyl, 2-naphthylethan-l-yl, 2- naphthylethen-l-yl, naphthobenzyl, 2-naphthophenylethan-l-yl and the like. Where specific alkyl moieties are intended, the nomenclature arylalkanyl, arylalkenyl and/or arylalkynyl is used. In certain embodiments, an arylalkyl group is (C7-C30) arylalkyl, e.g., the alkanyl, alkenyl or alkynyl moiety of the arylalkyl group is (C1-C1 ₀ ) and the aryl moiety is (C6-C ₂₀ ). In certain embodiments, an arylalkyl group is (C7-C2 ₀ ) arylalkyl, e.g., the alkanyl, alkenyl or alkynyl moiety of the arylalkyl group is (Ci-C ₈ ) and the aryl moiety is (C ₆ -Ci ₂ ).

"Arylaryl" by itself or as part of another substituent, refers to a monovalent hydrocarbon group derived by the removal of one hydrogen atom from a single carbon atom of a ring system in which two or more identical or non-identical aromatic ring systems are joined directly together by a single bond, where the number of such direct ring junctions is one less than the number of aromatic ring systems involved. Typical arylaryl groups include, but are not limited to, biphenyl, triphenyl, phenyl-napthyl, binaphthyl, biphenyl-napthyl, and the like. When the number of carbon atoms in an arylaryl group are specified, the numbers refer to the carbon atoms comprising each aromatic ring. For example, (C5-C14) arylaryl is an arylaryl group in which each aromatic ring comprises from 5 to 14 carbons, e.g., biphenyl, triphenyl, binaphthyl, phenylnapthyl, etc. In certain embodiments, each aromatic ring system of an arylaryl group is independently a (C5-C14) aromatic. In certain embodiments, each aromatic ring system of an arylaryl group is independently a (C5-C1 ₀ ) aromatic. In certain embodiments, each aromatic ring system is identical, e.g., biphenyl, triphenyl, binaphthyl, trinaphthyl, etc.

"Cycloalkyl" by itself or as part of another substituent refers to a saturated or unsaturated cyclic alkyl radical. Where a specific level of saturation is intended, the nomenclature

"cycloalkanyl" or "cycloalkenyl" is used. Typical cycloalkyl groups include, but are not limited to, groups derived from cyclopropane, cyclobutane, cyclopentane, cyclohexane and the like. In certain embodiments, the cycloalkyl group is (C ₃ -C1 ₀ ) cycloalkyl. In certain embodiments, the cycloalkyl group is (C ₃ -C7) cycloalkyl.

"Cycloheteroalkyl" or "heterocyclyl" by itself or as part of another substituent, refers to a saturated or unsaturated cyclic alkyl radical in which one or more carbon atoms (and any associated hydrogen atoms) are independently replaced with the same or different heteroatom. Typical heteroatoms to replace the carbon atom(s) include, but are not limited to, N, P, O, S, Si, etc. Where a specific level of saturation is intended, the nomenclature "cycloheteroalkanyl" or "cycloheteroalkenyl" is used. Typical cycloheteroalkyl groups include, but are not limited to, groups derived from epoxides, azirines, thiiranes, imidazolidine, morpholine, piperazine, piperidine, pyrazolidine, pyrrolidine, quinuclidine and the like.

"Heteroalkyl, Heteroalkanyl, Heteroalkenyl and Heteroalkynyl" by themselves or as part of another substituent refer to alkyl, alkanyl, alkenyl and alkynyl groups, respectively, in which one or more of the carbon atoms (and any associated hydrogen atoms) are independently replaced with the same or different heteroatomic groups. Typical heteroatomic groups which can be included in these groups include, but are not limited to, -0-, -S-, -S-S-, -0-S-, -NR 37 R 38 -, .=N-N=, -N=N-, -N=N-NR ³⁹ R ⁴⁰ , -PR ⁴¹ -, -P(0) ₂ -, -POR ⁴² -, -0-P(0) ₂ -, -S-0-, -S-(O)-, -S0 ₂ -, - SnR ⁴³ R ⁴⁴ - and the like, where R ³⁷ , R ³⁸ , R ³⁹ , R ⁴⁰ , R ⁴¹ , R ⁴² , R ⁴³ and R ⁴⁴ are independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl.

"Heteroaryl" by itself or as part of another substituent, refers to a monovalent heteroaromatic radical derived by the removal of one hydrogen atom from a single atom of a heteroaromatic ring system. Typical heteroaryl groups include, but are not limited to, groups derived from acridine, arsindole, carbazole, β-carboline, chromane, chromene, cinnoline, furan, imidazole, indazole, indole, indoline, indolizine, isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazole, xanthene, benzodioxole and the like. In certain embodiments, the heteroaryl group is from 5-20 membered heteroaryl. In certain embodiments, the heteroaryl group is from 5-10 membered heteroaryl. In certain embodiments, heteroaryl groups are those derived from thiophene, pyrrole,

benzothiophene, benzofuran, indole, pyridine, quinoline, imidazole, oxazole and pyrazine.

"Heteroarylalkyl" by itself or as part of another substituent, refers to an acyclic alkyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp ³ carbon atom, is replaced with a heteroaryl group. Where specific alkyl moieties are intended, the nomenclature heteroarylalkanyl, heteroarylalkenyl and/or heterorylalkynyl is used. In certain embodiments, the heteroarylalkyl group is a 6-30 membered heteroarylalkyl, e.g., the alkanyl, alkenyl or alkynyl moiety of the heteroarylalkyl is 1-10 membered and the heteroaryl moiety is a 5-20-membered heteroaryl. In certain embodiments, the heteroarylalkyl group is 6-20 membered heteroarylalkyl, e.g., the alkanyl, alkenyl or alkynyl moiety of the heteroarylalkyl is 1-8 membered and the heteroaryl moiety is a 5-12-membered heteroaryl.

"Aromatic Ring System" by itself or as part of another substituent, refers to an unsaturated cyclic or polycyclic ring system having a conjugated π electron system. Specifically included within the definition of "aromatic ring system" are fused ring systems in which one or more of the rings are aromatic and one or more of the rings are saturated or unsaturated, such as, for example, fluorene, indane, indene, phenalene, etc. Typical aromatic ring systems include, but are not limited to, aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as- indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, trinaphthalene and the like.

"Heteroaromatic Ring System" by itself or as part of another substituent, refers to an aromatic ring system in which one or more carbon atoms (and any associated hydrogen atoms) are independently replaced with the same or different heteroatom. Typical heteroatoms to replace the carbon atoms include, but are not limited to, N, P, O, S, Si, etc. Specifically included within the definition of "heteroaromatic ring systems" are fused ring systems in which one or more of the rings are aromatic and one or more of the rings are saturated or unsaturated, such as, for example, arsindole, benzodioxan, benzofuran, chromane, chromene, indole, indoline, xanthene, etc. Typical heteroaromatic ring systems include, but are not limited to, arsindole, carbazole, β-carboline, chromane, chromene, cinnoline, furan, imidazole, indazole, indole, indoline, indolizine, isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazole, xanthene and the like.

"Substituted" refers to a group in which one or more hydrogen atoms are independently replaced with the same or different substituent(s). Typical substituents include, but are not limited to, alkylenedioxy (such as methylenedioxy), -M, -R ⁶⁰ , -O , =0, -OR ⁶⁰ , -SR ⁶⁰ , -S ^" , =S, -NR ⁶⁰ R ⁶¹ , =NR ⁶⁰ , -CF ₃ , -CN, -OCN, -SCN, -NO, -N0 ₂ ,

=N ₂ , -N ₃ , -S(0) ₂ 0 ^" , -S(0) ₂ OH, -S(0) ₂ R ⁶⁰ , -OS(0) ₂ 0 ^" , -OS(0) ₂ R ⁶⁰ , -P(0)(0 ) ₂ , -P(O)(OR ⁶⁰ )(O ), -OP(O)(OR ⁶⁰ )(OR ⁶¹ ), -C(0)R ⁶⁰ , -C(S)R ⁶⁰ , -C(0)OR ⁶⁰ , -C(O)NR ⁶⁰ R ⁶¹ ,-C(O)O ^" , -C(S)OR ⁶⁰ , -NR ⁶² C(O)NR ⁶⁰ R ⁶¹ , -NR ⁶² C(S)NR ⁶⁰ R ⁶¹ , -NR ⁶² C(NR ⁶³ )NR ⁶⁰ R ⁶¹ and -C(NR ⁶² )NR ⁶⁰ R ⁶¹ where M is halogen; R ⁶⁰ , R ⁶¹ , R ⁶² and R ⁶³ are independently hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted

cycloheteroalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl, or optionally R ⁶⁰ and R ⁶¹ together with the nitrogen atom to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring; and R ⁶⁴ and R ⁶⁵ are independently hydrogen, alkyl, substituted alkyl, aryl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl, or optionally R ⁶⁴ and R ⁶⁵ together with the nitrogen atom to which they are bonded form a cycloheteroalkyl or substituted

cycloheteroalkyl ring. In certain embodiments, substituents include -M, -R ⁶⁰ ,

=0, -OR ⁶⁰ , -SR ⁶⁰ , -S ^" , =S, -NR ⁶⁰ R ⁶¹ , =NR ⁶⁰ , -CF ₃ , -CN, -OCN, -SCN, -NO, -N0 ₂ , =N ₂ , -N ₃ , -S(0) ₂ R ^bU , -OS(0) ₂ 0 ^" , -OS(0) ₂ R ^bU , -P(0)(0 ) ₂ , -P(0)(OR ^t,u )(0 ), -OP(0)(OR ^t,u )(OR ^t ' ¹ ), -C(0)R ⁶⁰ , -C(S)R ⁶⁰ , -C(0)OR ⁶⁰ , -C(O)NR ⁶⁰ R ⁶¹ ,-C(O)O ^~ , -NR ⁶² C(O)NR ⁶⁰ R ⁶¹ . In certain embodiments, substituents include -M, -R ⁶⁰ ,

=0, -OR ⁶⁰ , -SR ⁶⁰ , -NR ⁶⁰ R ⁶¹ , -CF ₃ , -CN, -N0 ₂ , -S(0) ₂ R ⁶⁰ , -P(O)(OR ⁶⁰ )(O ^" ), -OP(O)(OR ⁶⁰ )(OR ⁶¹ ), -C(0)R ⁶⁰ , -C(0)OR ⁶⁰ , -C(O)NR ⁶⁰ R ⁶¹ ,-C(O)O ^~ . In certain embodiments, substituents include -M, -R ⁶⁰ ,

=0, -OR ⁶⁰ , -SR ⁶⁰ , -NR ⁶⁰ R ⁶¹ , -CF ₃ , -CN, -N0 ₂ , -S(0) ₂ R ⁶⁰ , -OP(O)(OR ⁶⁰ )(OR ⁶¹ ), -C(0)R ⁶⁰ , -C(0 )OR ⁶⁰ ,-C(0)0 ^" , where R ⁶⁰ , R ⁶¹ and R ⁶² are as defined above. For example, a substituted group may bear a methylenedioxy substituent or one, two, or three substituents selected from a halogen atom, a (l-4C)alkyl group and a (l-4C)alkoxy group.

"PK profile" refers to a profile of drug concentration in blood or plasma. Such a profile can be a relationship of drug concentration over time (i.e., a "concentration-time PK profile") or a relationship of drug concentration versus number of doses ingested (i.e., a "concentration-dose PK profile"). A PK profile is characterized by PK parameters.

"PK parameter" refers to a measure of drug concentration in blood or plasma, such as: 1)

"drug Cmax", the maximum concentration of drug achieved in blood or plasma; 2) "drug Tmax", the time elapsed following ingestion to achieve Cmax; and 3) "drug exposure", the total concentration of drug present in blood or plasma over a selected period of time, which can be measured using the area under the curve (AUC) of a time course of drug release over a selected period of time (t). Modification of one or more PK parameters provides for a modified PK profile.

"Pharmacodynamic (PD) profile" refers to a profile of the efficacy of a drug in a patient (or subject or user), which is characterized by PD parameters. "PD parameters" include "drug Emax" (the maximum drug efficacy), "drug EC50" (the concentration of drug at 50% of the Emax) and side effects.

"Pharmaceutical composition" refers to at least one compound and can further comprise a pharmaceutically acceptable carrier, with which the compound is administered to a patient.

"Pharmaceutically acceptable salt" refers to a salt of a compound, which possesses the desired pharmacological activity of the compound. Such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1 ,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-l-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or (2) salts formed when an acidic proton present in the compound is replaced by a metal ion, e.g. , an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine,

N-methylglucamine and the like.

The term "solvate" as used herein refers to a complex or aggregate formed by one or more molecules of a solute, e.g. a prodrug or a pharmaceutically-acceptable salt thereof, and one or more molecules of a solvent. Such solvates are typically crystalline solids having a substantially fixed molar ratio of solute and solvent. Representative solvents include by way of example, water, methanol, ethanol, isopropanol, acetic acid, and the like. When the solvent is water, the solvate formed is a hydrate.

"Pharmaceutically acceptable carrier" refers to a diluent, adjuvant, excipient or vehicle with, or in which a compound is administered.

"Preventing" or "prevention" or "prophylaxis" refers to a reduction in risk of occurrence of a condition, such as pain.

"Prodrug" refers to a derivative of an active agent that requires a transformation within the body to release the active agent. In certain embodiments, the transformation is an enzymatic transformation. Prodrugs are frequently, although not necessarily, pharmacologically inactive until converted to the active agent.

"Promoiety" refers to a form of protecting group that when used to mask a functional group within an active agent converts the active agent into a prodrug. Typically, the promoiety will be attached to the drug via bond(s) that are cleaved by enzymatic or non-enzymatic means in vivo.

"Treating" or "treatment" of any condition, such as pain, refers, in certain embodiments, to ameliorating the condition (i.e., arresting or reducing the development of the condition). In certain embodiments "treating" or "treatment" refers to ameliorating at least one physical parameter, which may not be discernible by the patient. In certain embodiments, "treating" or "treatment" refers to inhibiting the condition, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both. In certain embodiments, "treating" or "treatment" refers to delaying the onset of the condition.

"Therapeutically effective amount" means the amount of a compound that, when administered to a patient for preventing or treating a condition such as pain, is sufficient to effect such treatment. The "therapeutically effective amount" will vary depending on the compound, the condition and its severity and the age, weight, etc. , of the patient.

DETAILED DESCRIPTION

Before exemplary embodiments of the present invention are described, it is to be understood that this invention is not limited to particular embodiments described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.

Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limits of that range is also specifically disclosed. Each smaller range between any stated value or intervening value in a stated range and any other stated or intervening value in that stated range is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included or excluded in the range, and each range where either, neither or both limits are included in the smaller ranges is also encompassed within the invention, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the invention.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, some potential and exemplary methods and materials may now be described. Any and all publications mentioned herein are incorporated herein by reference to disclose and describe the methods and/or materials in connection with which the publications are cited. It is understood that the present disclosure supersedes any disclosure of an incorporated publication to the extent there is a contradiction.

It must be noted that as used herein and in the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a membrane anchored polynucleotide" includes a plurality of such membrane-anchored polynucleotides and reference to "the polynucleotide" includes reference to one or more polynucleotides, and so forth.

It is further noted that the claims may be drafted to exclude any element which may be optional. As such, this statement is intended to serve as antecedent basis for use of such exclusive terminology as "solely", "only" and the like in connection with the recitation of claim elements, or the use of a "negative" limitation.

The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention.

Further, the dates of publication provided may be different from the actual publication dates which may need to be independently confirmed. To the extent such publications may set out definitions of a term that conflicts with the explicit or implicit definition of the present disclosure, the definition of the present disclosure controls.

As will be apparent to those of skill in the art upon reading this disclosure, each of the individual embodiments described and illustrated herein has discrete components and features which may be readily separated from or combined with the features of any of the other several embodiments without departing from the scope or spirit of the present invention. Any recited method can be carried out in the order of events recited or in any other order which is logically possible.

CELL PERMEABLE CYCLIC PEPTIDE SCAFFOLDS

As summarized above, aspects of the present disclosure include cell permeable cyclic peptide scaffolds where the cell permeable cyclic peptide scaffolds include a hexapeptide composed of naturally or non- naturally occurring amino acids. Cell permeable cyclic peptide scaffolds according to some embodiments are permeable into cells. In certain embodiments, the cell permeable cyclic peptide scaffolds described herein are permeable into the nucleus of the cells. In embodiments of the present disclosure, cells permeable to the subject cyclic peptide scaffolds include eukaryotic cells (e.g., mammalian cells) and/or prokaryotic cells (e.g., bacterial cells or archaeal cells). Cells permeable to the subject cyclic peptide scaffolds may be obtained from an in vitro source (e.g., a suspension of cells from laboratory cells grown in culture) or from an in vivo source (e.g., a mammalian subject, a human subject, etc.). In some embodiments, the cells permeable to the subject cyclic peptide scaffolds are obtained from an in vitro source. In vitro sources include, but are not limited to, prokaryotic (e.g., bacterial, archaeal) cell cultures, environmental samples that contain prokaryotic and/or eukaryotic (e.g., mammalian, protest, fungal, etc.) cells, eukaryotic cell cultures (e.g., cultures of established cell lines, cultures of known or purchased cell lines, cultures of immortalized cell lines, cultures of primary cells, cultures of laboratory yeast, etc.), tissue cultures, and the like.

In some embodiments, cells permeable to the subject cyclic peptide scaffolds are obtained from an in vivo source and can include samples obtained from tissues (e.g., cell suspension from a tissue biopsy, cell suspension from a tissue sample, etc.) and/or body fluids (e.g., whole blood, fractionated blood, plasma, serum, saliva, lymphatic fluid, interstitial fluid, etc.). In some cases, cells, fluids, or tissues derived from a subject are cultured, stored, or manipulated prior to evaluation. In vivo sources include living multi-cellular organisms and can yield non-diagnostic or diagnostic cellular samples.

In certain embodiments the source of the cells is a "mammal" or "mammalian", where these terms are used broadly to describe organisms which are within the class mammalia, including the orders carnivore (e.g., dogs and cats), rodentia (e.g., mice, guinea pigs, and rats), and primates (e.g., humans, chimpanzees, and monkeys). In some instances, the subjects are humans. The methods may be applied to samples obtained from human subjects of both genders and at any stage of development (i.e., neonates, infant, juvenile, adolescent, adult), where in certain embodiments the human subject is a juvenile, adolescent or adult. While the present invention may be applied to samples from a human subject, it is to be understood that the methods may also be carried-out on samples from other animal subjects (that is, in "non-human subjects") such as, but not limited to, birds, mice, rats, dogs, cats, livestock and horses.

In embodiments, the cyclic peptide scaffold is a compound of Formula I:

Cyclo [Z-Y-X-Pro-Y-Phe] Formula I wherein:

Pro is L-proline or D-proline;

Phe is -phenylalanine or D-phenylalanine;

each Ri is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl, or optionally, R ¹ together with the atoms to which it is bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring;

each R2 is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl, or optionally, R ¹ together with the atoms to which it is bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring;

each R ₃ is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl, or optionally, R ¹ together with the atoms to which it is bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring;

A is selected from -NR _a -, -O- or -S-;

B is selected from -NRt,-, -O- or -S-;

C is selected from -NR _C -, -O- or -S-;

each R _a , R _b , R _c is independently selected from hydrogen, alkyl, substituted alkyl, aryl and substituted aryl, or

Ri and R _a together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring;

R2 and R _b together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring;

R ₃ and R _c together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring;

n is an integer from one to 5 and a is an integer from one to 5; p is an integer from one to 5 and b is an integer from one to 5; and

r is an integer from one to 5 and c is an integer from one to 5 ;

or a pharmaceutical acceptable salt, solvate or hydrate thereof.

In some embodiments in the compounds of Formula I, each Ri is independently selected from a side chain of an amino acid selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glycine, glutamine, glutamic acid, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine. In some instances, each Ri is independently selected from a side chain of glycine, leucine or phenylalanine. In one example, Ri is a side chain of glycine. In another example, Ri is a side chain of leucine. In yet another example, Ri is a side chain of phenylalanine.

In some embodiments in the compounds of Formula I, each R2 is independently selected from a side chain of an amino acid selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glycine, glutamine, glutamic acid, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine. In some instances, R ₂ is selected from a side chain of leucine or glycine. In one example, R2 is a side chain of leucine. In another example, R2 is a side chain of glycine.

In some embodiments in the compounds of Formula I, each R ₃ is independently selected from a side chain of an amino acid selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glycine, glutamine, glutamic acid, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine. In some instances, R ₃ is independently selected from a side chain of glycine, alanine or phenylalanine. In one example, R ₃ is a side chain of glycine. In another example, R ₃ is a side chain of alanine. In yet another example, R ₃ is a side chain of phenylalanine.

In embodiments, n ranges from 1 to 10, such as where n is 1, such as where n is 2, such as where n is 3, such as where n is 4, such as where n is 5, such as where n is 6, such as where n is 7, such as where n is 8, such as where n is 9 and including where n is 10. In certain embodiments, n ranges from 1 to 5. In one example, n is 1. In this example where n is 1, X may be a naturally occurring amino acid, as described below. In another example, n is 2. In this example where n is 2, X may be a non-naturally occurring amino acid, such as a non-naturally occurring glycine or phenylalanine residue.

In embodiments, p ranges from 1 to 10, such as where p is 1, such as where p is 2, such as where p is 3, such as where p is 4, such as where p is 5, such as where p is 6, such as where p is 7, such as where p is 8, such as where p is 9 and including where p is 10. In certain embodiments, p ranges from 1 to 5. In one example, p is 1. In this example where p is 1, Y may be a naturally occurring amino acid, such as a glycine or leucine residue. In another example, p is 2. In this example where p is 2, Y may be a non-naturally occurring amino acid.

In embodiments, r ranges from 1 to 10, such as where r is 1, such as where r is 2, such as where r is 3, such as where r is 4, such as where r is 5, such as where r is 6, such as where r is 7, such as where r is 8, such as where r is 9 and including where r is 10. In certain embodiments, r ranges from 1 to 5. In one example, r is 1. In this example where r is 1, Z may be a naturally occurring amino acid, as described below. In another example, r is 2. In this example where r is 2, Z may be a non-naturally occurring amino acid, such as a non-naturally occurring glycine or phenylalanine residue.

In certain embodiments, n is 2 and each Ri is selected from a side chain of glycine or phenylalanine. In other embodiments, r is 2 and each R ₃ is selected from a side chain of glycine or phenylalanine. In still other embodiments, p is 1 and R ₂ is glycine or leucine.

A may be -NR _a -, -O- or -S-. In some instances, A is O. In other instances, A is S. In certain instances, A is NR _a where R _a is hydrogen, alkyl or aryl. In certain embodiments, R _a is hydrogen. In other embodiments, R _a is aryl, such as benzyl. In yet other instances, R _a is alkyl, such as methyl or propyl.

B may be -NR _b -, -O- or -S-. In some instances, B is O. In other instances, B is S. In certain instances, B is NR _b where R _b is hydrogen, alkyl or aryl. In certain embodiments, R _b is hydrogen. In other embodiments, R _b is aryl, such as benzyl. In yet other instances, R _b is alkyl, such as methyl or propyl.

C may be -NR _b -, -O- or -S-. In some instances, C is O. In other instances, C is S. In certain instances, C is NR _C where R _c is hydrogen, alkyl or aryl. In certain embodiments, R _c is hydrogen. In other embodiments, R _c is aryl, such as benzyl. In yet other instances, R _c is alkyl, such as methyl or propyl.

In some embodiments, X is a residue of a D-amino acid or L-amino acid selected from alanine, arginine, asparagine, aspartic acid, cysteine, glycine, glutamine, glutamic acid, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, β-homophenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine or an N-alkyl derivative thereof. In some instances, X is a D-amino acid selected from alanine, arginine, asparagine, aspartic acid, cysteine, glycine, glutamine, glutamic acid, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, β- homophenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine or an N-alkyl derivative thereof. For example, X may be D-leucine or an N-alkyl derivative thereof, such as N-methyl D-leucine. In other instances, X is an L-amino acid selected from alanine, arginine, asparagine, aspartic acid, cysteine, glycine, glutamine, glutamic acid, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, β-homophenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine or an N-alkyl derivative thereof. For example, X may be L- leucine or an N-alkyl derivative thereof, such as N-methyl L-leucine. In other instances, X is L- β-homophenylalanine or an alkyl derivative thereof. In yet other instances, X is glycine or an N- alkyl derivative thereof, such as N-benzyl glycine.

In some embodiments, Y is a residue of a D-amino acid or L-amino acid selected from alanine, arginine, asparagine, aspartic acid, cysteine, glycine, glutamine, glutamic acid, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, β-homophenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine or an N-alkyl derivative thereof. In some instances, Y is a D-amino acid selected from alanine, arginine, asparagine, aspartic acid, cysteine, glycine, glutamine, glutamic acid, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, β- homophenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine or an N-alkyl derivative thereof. For example, Y may be D-leucine or an N-alkyl derivative thereof, such as N-methyl D-leucine. In other instances, Y is an L-amino acid selected from alanine, arginine, asparagine, aspartic acid, cysteine, glycine, glutamine, glutamic acid, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, β-homophenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine or an N-alkyl derivative thereof. For example, Y may be L- leucine or an N-alkyl derivative thereof, such as N-methyl L-leucine. In yet other instances, Y is glycine or an N-alkyl derivative thereof, such as N-benzyl glycine.

In some embodiments, Z is a residue of a D-amino acid or L-amino acid selected from alanine, arginine, asparagine, aspartic acid, cysteine, glycine, glutamine, glutamic acid, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, β-homophenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine or an N-alkyl derivative thereof. In some instances, Z is a D-amino acid selected from alanine, arginine, asparagine, aspartic acid, cysteine, glycine, glutamine, glutamic acid, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, β- homophenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine or an N-alkyl derivative thereof. For example, Z may be D-alanine or an N-alkyl derivative thereof, such as N-methyl D-leucine. In other instances, Z is an L-amino acid selected from alanine, arginine, asparagine, aspartic acid, cysteine, glycine, glutamine, glutamic acid, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, β-homophenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine or an N-alkyl derivative thereof. For Example, Z may be L- alanine or an N-alkyl derivative thereof, such as N-methyl L-alanine. In yet other instances, Z is L- -homophenylalanine or an alkyl derivative thereof. In still other instances, Z is glycine or an N-alkyl derivative thereof, such as N-propyl glycine.

In certain embodiments, a cell permeable cyclic peptide scaffold of interest includes a compound of Formula 1 :

Formula 1.

or a pharmaceutical acceptable salt, solvate or hydrate thereof.

In other embodiments, a cell permeable cyclic peptide scaffold of interest includes a compound of Formula 2:

Formula 2 or a pharmaceutical acceptable salt, solvate or hydrate thereof.

In certain embodiments, cell permeable cyclic peptide scaffolds of interest include the compounds as set forth in Table 1 , wherein each compound has a cyclic hexapeptide structure, (i.e., cyclo[A-B-C-X-Y-Z]) having a sequence of amino acids as set forth in Table 1, wherein:

LA02 = Pro-peptoid

MA = N-methyl L-alanine

Ma = N-methyl D-alanine

A = L-alanine

a = D-alanine

BHF = L- -Homophenylalanine

ML*** = N-methyl L-leucine

Ml = N-methyl D-leucine

L*** = L-leucine

1 = D-leucine

LA08 = Benzylpeptoid

L-proline

D-proline

L- Phenylalanine.

Table 1

Compound Compound

No. Cyclic Peptide Sequence No. Cyclic Peptide Sequence

1 BHF,L***,BHF,p,L***,F 621 MA,LA08,L***,p,l,F

2 BHF,l,Ml,p,Ml,F 622 Ma,LA08,L***,P,l,F

3 A,L***,L***,p,LA08,F 623 a,LA08,L***,P,LA08,F

4 BHF,l,Ml,p,l,F 624 A,L***,Ml,p,Ml,F

5 BHF,L***,1,P,L***,F 625 LA02,ML***,LA08,p,LA08,F

6 Ma,Ml,L***,P,l,F 626 A,1,LA08,P,LA08,F

7 A,L***,l,p,l,F 627 LA02,LA08,ML***,P,1,F

8 A,M1,BHF,P,1,F 628 BHF,Ml,BHF,p,Ml,F

9 A,Ml,l,p,ML***,F 629 LA02,ML***,L***,p,l,F

10 a,Ml,l,P,Ml,F 630 Ma,L***,Ml,p,l,F

11 MA,M1,M1,P,M1,F 631 LA02,Ml,LA08,p,ML***,F

12 A,l,BHF,p,l,F 632 MA,Ml,Ml,p,Ml,F BHF,1,M1,P,M1,F 633 a,ML***,l,p,Ml,F

MA,M1,M1,P,ML***,F 634 A,ML***,L***,P,1,F

MA,LA08,M1,P,1,F 635 Ma,l,l,p,l,F

MA,M1,L***,P,M1,F 636 BHF,M1,M1,P,M1,F

BHF,1,ML***,P,ML***,F 637 LA02,LA08,LA08,p,l,F

BHF,L***,BHF,p,l,F 638 a,ML***,l,P,Ml,F

MA,LA08,L***,P,M1,F 639 a,Ml,BHF,P,l,F

BHF,M1,M1,P,M1,F 640 a,LA08,LA08,P,LA08,F

LA02,1,M1,P,M1,F 641 LA02,1,LA08,P,LA08,F a,Ml,ML***,p,l,F 642 LA02,1,1,P,LA08,F a,L***,L***,p,Ml,F 643 LA02,Ml,Ml,p,LA08,F

BHF,Ml,Ml,p,Ml,F 644 LA02,Ml,LA08,p,LA08,F

BHF,M1,M1,P,M1,F 645 MA,1,LA08,P,LA08,F

Ma,L***,ML***,P,Ml,F 646 A,l,LA08,p,Ml,F

MA,ML***,LA08,P,LA08,F 647 A,L***,M1,P,M1,F

MA,M1,M1,P,M1,F 648 Ma,ML***,BHF,p,LA08,F

BHF,Ml,Ml,p,l,F 649 MA,ML***,BHF,p,LA08,F a,ML***,L***,p,l,F 650 MA,L***,ML***,p,LA08,F

Ma,Ml,L***,P,ML***,F 651 a,Ml,Ml,P,Ml,F

A,Ml,Ml,p,l,F 652 Ma,Ml,Ml,p,Ml,F

A,Ml,L***,p,Ml,F 653 a,L***,Ml,P,l,F

A,LA08,Ml,p,L***,F 654 A,Ml,LA08,p,Ml,F

A,M1,L***,P,M1,F 655 Ma,L***,l,P,LA08,F a,Ml,BHF,p,Ml,F 656 Ma,l,l,P,L***,F

Ma,ML***,l,P,ML***,F 657 Ma,l,l,p,LA08,F

A,M1,M1,P,ML***,F 658 MA,Ml,LA08,p,LA08,F

MA,1,M1,P,ML***,F 659 BHF,Ml,l,p,Ml,F

A,Ml,Ml,p,LA08,F 660 LA02,LA08,1,P,LA08,F

MA,M1,ML***,P,M1,F 661 LA02,l,BHF,p,L***,F

BHF,M1,M1,P,M1,F 662 LA02,LA08,LA08,p,l,F

Ma,Ml,l,P,Ml,F 663 LA02,l,Ml,p,Ml,F

Ma,Ml,l,P,Ml,F 664 LA02,Ml,ML***,p,ML***,F

LA02,M1,LA08,P,M1,F 665 A,LA08,ML***,P,M1,F

LA02,M1,LA08,P,M1,F 666 a,Ml,ML***,p,L***,F

A,L***,BHF,p,l,F 667 a,LA08,LA08,p,l,F

MA,M1,M1,P,L***,F 668 BHF,ML***,LA08,P,1,F

Ma,Ml,Ml,P,Ml,F 669 BHF,L*** ML***,p,LA08,F

Ma,ML***,Ml,P,Ml,F 670 BHF,1,BHF,P,1,F

MA,1,M1,P,1,F 671 MA,L***,LA08,p,LA08,F

A,M1,ML***,P,M1,F 672 A,l,LA08,p,L***,F

A,L***,Ml,p,ML***,F 673 BHF,1,1,P,LA08,F

MA,L***,M1,P,M1,F 674 a,L***,LA08,P,LA08,F

A,l,LA08,p,l,F 675 LA02,LA08,LA08,P,LA08,F Ma,Ml,ML***,P,Ml,F 676 LA02,LA08,LA08,P,L***,F

MA,M1,LA08,P,ML***,F 677 LA02,L***,L***,p,LA08,F

A,M1,BHF,P,M1,F 678 a,L***,l,P,Ml,F

BHF,U,p,Ml,F 679 BHF,LA08,1,P,1,F a,L***,BHF,p,l,F 680 A,L***,1,P,M1,F

a,L***,LA08,P,L***,F 681 a,Ml,l,P,l,F

BHF,L***,l,p,Ml,F 682 LA02,ML***, LA08,P,LA08,F a,Ml,L***,p,Ml,F 683 Ma,ML***,l,P,l,F

MA,ML***,M1,P,M1,F 684 a,Ml,LA08,p,LA08,F

Ma,l,ML***,P,ML***,F 685 A,L***,l,p,Ml,F

BHF,Ml,Ml,p,Ml,F 686 Ma,LA08,L***,P,l,F

MA,ML***,L***,p,Ml,F 687 LA02,ML***, LA08,P,LA08,F a,ML***,Ml,P,l,F 688 BHF,L***,BHF,p,Ml,F

A,Ml,Ml,p,Ml,F 689 a,ML***,l,P,L***,F

A,ML***,BHF,P,L***,F 690 Ma,L***,Ml,p,L***,F

A,L***,L***,p,l,F 691 LA02,l,BHF,p,Ml,F

Ma,ML***,Ml,P,L***,F 692 Ma,l,BHF,p,LA08,F

A,l,ML***,p,l,F 693 A,L***,LA08,P,1,F

A,Ml,BHF,p,Ml,F 694 Ma,L***,LA08,P,LA08,F

MA,1,M1,P,LA08,F 695 a,L***,l,P,ML***,F

A,Ml,BHF,p,Ml,F 696 A,LA08,1,P,LA08,F

LA02,M1,BHF,P,L***,F 697 BHF,L***,M1,P,ML***,F

A,Ml,l,p,LA08,F 698 LA02,ML***,BHF,P,L***,F

A,Ml,l,p,Ml,F 699 BHF,L***,ML***,P,1,F

A,Ml,L***,p,ML***,F 700 LA02,Ml,L***,p,ML***,F

Ma,Ml,L***,P,LA08,F 701 LA02,Ml,ML***,p,Ml,F

A,l,Ml,p,Ml,F 702 BHF,L***,LA08,P,1,F a,Ml,L***,P,Ml,F 703 MA,l,BHF,p,LA08,F

MA,Ml,Ml,p,Ml,F 704 A,L***,LA08,p,l,F

A,L***,LA08,p,Ml,F 705 LA02,L***,BHF,P,L***,F

MA,L***,M1,P,M1,F 706 MA,M1,1,P,LA08,F

MA,M1,M1,P,LA08,F 707 LA02,l,Ml,p,Ml,F

LA02,M1,L***,P,1,F 708 a,l,BHF,p,l,F

Ma,L***,Ml,P,ML***,F 709 BHF,L***, L***,P,LA08,F

Ma,ML***,L***,P,Ml,F 710 LA02,LA08,BHF,P,L***,F

A,M1,BHF,P,M1,F 711 a,LA08,l,P,LA08,F

Ma,Ml,Ml,P,Ml,F 712 a,Ml,l,P,L***,F

a,Ml,BHF,p,Ml,F 713 BHF,1,BHF,P,LA08,F

BHF,M1,M1,P,M1,F 714 LA02,L***,1,P,1,F a,Ml,L***,P,ML***,F 715 BHF,LA08,BHF,P,L***,F

BHF,L***,LA08,P,L***,F 716 A,LA08,ML***,P,ML***,F

A,Ml,L***,p,l,F 717 a,l,LA08,P,LA08,F

LA02,M1,BHF,P,M1,F 718 LA02,l,L***,p,L***,F

A,M1,L***,P,ML***,F 719 BHF,M1,BHF,P,1,F 100 MA,ML***,1,P,M1,F 720 a,l,BHF,p,Ml,F

101 Ma,Ml,Ml,P,Ml,F 721 BHF,LA08,1,P,M1,F

102 a,Ml,BHF,p,Ml,F 722 A,ML***,LA08,p,Ml,F

103 LA02,M1,M1,P,M1,F 723 MA,L***,L***,p,Ml,F

104 MA,M1,ML***,P,LA08,F 724 A,M1,BHF,P,L***,F

105 LA02,L***,1,P,L***,F 725 BHF,L***,ML***,P,LA08,F

106 MA,l,L***,p,ML***,F 726 BHF,LA08,Ml,p,Ml,F

107 Ma,L***,Ml,p,ML***,F 727 LA02,L***,BHF,p,l,F

108 MA,M1,1,P,ML***,F 728 a,LA08,ML*** p,ML***,F

109 MA,L***,M1,P,ML***,F 729 A,LA08,ML***,P,1,F

110 BHF,L***,M1,P,L***,F 730 A,Ml,Ml,p,Ml,F

111 Ma,ML***,Ml,P,LA08,F 731 LA02,LA08,L***,p,LA08,F

112 a,LA08,Ml,p,L***,F 732 BHF,l,ML***,p,LA08,F

113 LA02,1,M1,P,M1,F 733 Ma,L***,L***,p,Ml,F

114 A,L***,LA08,p,l,F 734 LA02,M1,M1,P,M1,F

115 a,ML***,Ml,P,LA08,F 735 BHF,M1,1,P,ML***,F

116 a,l,LA08,p,l,F 736 Ma,Ml,L***,p,l,F

117 a,Ml,LA08,p,l,F 737 BHF,LA08,ML***,P,L***,F

118 A,1,L***,P,L***,F 738 BHF,ML***,Ml,p,Ml,F

119 LA02,Ml,Ml,p,Ml,F 739 a,l,LA08,p,ML***,F

120 A,l,L***,p,L***,F 740 a,Ml,LA08,P,L***,F

121 LA02,M1,1,P,1,F 741 LA02,LA08,l,p,L***,F

122 a,Ml,BHF,P,Ml,F 742 BHF,l,L***,p,ML***,F

123 A,L***,LA08,p,LA08,F 743 LA02,l,L***,p,L***,F

124 A,l,L***,p,Ml,F 744 A,l,l,p,LA08,F

125 a,Ml,L***,p,l,F 745 LA02,L***,Ml,p,LA08,F

126 Ma,Ml,BHF,P,Ml,F 746 MA,ML***,BHF,p,LA08,F

127 Ma,Ml,l,P,LA08,F 747 a,L***, L***,P,LA08,F

128 MA,1,ML***,P,ML***,F 748 BHF,L***,1,P,LA08,F

129 BHF,Ml,Ml,p,Ml,F 749 LA02,M1,1,P,LA08,F

130 Ma,Ml,l,P,l,F 750 MA,Ml,L***,p,l,F

131 Ma,LA08,Ml,P,L***,F 751 a,LA08,l,p,Ml,F

132 Ma,L***,Ml,P,L***,F 752 LA02,L***,l,p,l,F

133 a,Ml,l,P,ML***,F 753 Ma,Ml,BHF,P,l,F

134 BHF,1,M1,P,1,F 754 MA,LA08,ML***,P,M1,F

135 BHF,l,L***,p,ML***,F 755 MA,LA08,l,p,LA08,F

136 a,Ml,LA08,p,ML***,F 756 Ma,Ml,BHF,p,l,F

137 MA,1,M1,P,M1,F 757 BHF,M1,L***,P,LA08,F

138 MA,M1,1,P,M1,F 758 LA02,Ml,BHF,p,Ml,F

139 BHF,M1,M1,P,M1,F 759 BHF,l,l,p,L***,F

140 A,L***,M1,P,L***,F 760 a,LA08,BHF,p,ML***,F

141 a,Ml,L***,p,ML***,F 761 a,Ml,Ml,P,Ml,F

142 MA,L***,M1,P,1,F 762 BHF,Ml,L***,p,l,F

143 LA02,M1,1,P,M1,F 763 a,LA08,l,P,LA08,F 144 Ma,LA08,l,P,Ml,F 764 Ma,L***,l,p,LA08,F

145 MA,M1,BHF,P,M1,F 765 LA02,ML***,M1,P,LA08,F

146 BHF,1,1,P,ML***,F 766 BHF,LA08,BHF,p,l,F

147 Ma,L***,l,P,ML***,F 767 A,L***,M1,P,1,F

148 Ma,L***,l,P,L***,F 768 A,M1,1,P,1,F

149 MA,1,LA08,P,ML***,F 769 Ma,ML***,LA08,p,Ml,F

150 BHF,Ml,Ml,p,Ml,F 770 A,ML***,LA08,P,1,F

151 MA,M1,1,P,M1,F 771 a,LA08,LA08,p,l,F

152 MA,M1,1,P,M1,F 772 BHF,L***,LA08,p,Ml,F

153 LA02,L***,L***,P,M1,F 773 Ma,l,BHF,P,Ml,F

154 a,LA08,Ml,P,Ml,F 774 A,1,BHF,P,1,F

155 MA,M1,M1,P,1,F 775 a,ML***,BHF,P,LA08,F

156 MA,M1,M1,P,1,F 776 A,Ml,LA08,p,Ml,F

157 Ma,l,Ml,P,Ml,F 777 BHF,M1,LA08,P,M1,F

158 LA02,l,L***,p,Ml,F 778 LA02,1,M1,P,M1,F

159 Ma,LA08,Ml,P,Ml,F 779 Ma,LA08,ML***,P,l,F

160 LA02,1,L***,P,ML***,F 780 LA02,Ml,l,p,l,F

161 A,l,ML***,p,Ml,F 781 BHF,ML***, LA08,p,LA08,F

162 Ma,Ml,BHF,P,Ml,F 782 MA,l,LA08,p,LA08,F

163 a,LA08,ML***,P,Ml,F 783 Ma,ML***,BHF,p,l,F

164 LA02,L***,1,P,M1,F 784 Ma,LA08,BHF,P,L***,F

165 Ma,Ml,BHF,P,Ml,F 785 LA02,l,l,p,LA08,F

166 A,Ml,Ml,p,Ml,F 786 a,L***,l,p,Ml,F

167 a,ML***,L***,p,ML***,F 787 Ma,l,L***,P,LA08,F

168 LA02,M1,M1,P,M1,F 788 LA02,ML***,1,P,L***,F

169 A,Ml,ML***,p,L***,F 789 LA02,l,BHF,p,L***,F

170 MA,1,1,P,LA08,F 790 BHF,LA08,L***,p,Ml,F

171 a,Ml,L***,P,LA08,F 791 LA02,Ml,LA08,p,ML***,F

172 A,L***,ML***,p,Ml,F 792 MA,M1,M1,P,M1,F

173 BHF,l,Ml,p,L***,F 793 BHF,LA08,LA08,p,l,F

174 a,LA08,Ml,p,ML***,F 794 A,1,1,P,M1,F

175 MA,ML***,LA08,P,LA08,F 795 a,L***,l,p,LA08,F

176 BHF,ML***,LA08,p,ML***,F 796 a,Ml,BHF,P,LA08,F

177 BHF,L***,Ml,p,l,F 797 MA,L***,1,P,L***,F

178 LA02,1,ML***,P,M1,F 798 BHF,M1,1,P,M1,F

179 Ma,ML***,L***,p,Ml,F 799 a,LA08,Ml,p,l,F

180 MA,1,ML***,P,LA08,F 800 A,1,BHF,P,ML***,F

181 A,ML***,M1,P,M1,F 801 A,LA08,Ml,p,L***,F

182 Ma,l,ML***,P,l,F 802 MA,Ml,LA08,p,L***,F

183 BHF,L***,l,p,LA08,F 803 MA,M1,BHF,P,M1,F

184 LA02,L***,l,p,ML***,F 804 A,LA08,1,P,1,F

185 LA02,ML***,l,p,ML***,F 805 A,1,L***,P,L***,F

186 Ma,l,ML***,p,ML***,F 806 BHF,M1,ML***,P,ML***,F

187 MA,Ml,L***,p,ML***,F 807 MA,M1,M1,P,M1,F 188 LA02,M1,BHF,P,M1,F 808 MA,ML***,BHF,p,l,F

189 LA02,ML***,l,p,LA08,F 809 A,1,BHF,P,LA08,F

190 MA,l,LA08,p,ML***,F 810 a,l,BHF,P,ML***,F

191 Ma,L***,Ml,P,LA08,F 811 a,LA08,Ml,P,LA08,F

192 Ma,Ml,Ml,P,l,F 812 BHF,Ml,l,p,ML***,F

193 A,L***,BHF,P,ML***,F 813 a,L***,Ml,p,l,F

194 a,Ml,l,p,ML***,F 814 a,l,BHF,P,LA08,F

195 A,M1,M1,P,L***,F 815 a,LA08,L***,p,L***,F

196 a,Ml,Ml,P,l,F 816 LA02,1,1,P,M1,F

197 A,Ml,ML***,p,l,F 817 A,l,BHF,p,Ml,F

198 Ma,L***,Ml,P,l,F 818 BHF,L***,LA08,p,LA08,F

199 A,L***,L***,p,Ml,F 819 LA02,l,LA08,p,LA08,F

200 A,1,L***,P,LA08,F 820 MA,L***,L***,p,LA08,F

201 A,ML***,M1,P,ML***,F 821 BHF,L***,Ml,p,ML***,F

202 LA02,M1,M1,P,1,F 822 A,1,1,P,L***,F

203 BHF,Ml,Ml,p,Ml,F 823 MA,L***,BHF,p,LA08,F

204 LA02,Ml,Ml,p,Ml,F 824 BHF,Ml,L***,p,ML***,F

205 LA02,M1,M1,P,M1,F 825 BHF,L***,L***,P,1,F

206 LA02,1,L***,P,1,F 826 a,Ml,Ml,P,Ml,F

207 a,Ml,Ml,p,Ml,F 827 MA,1,M1,P,1,F

208 a,LA08,ML***,P,ML***,F 828 Ma,L***,l,p,Ml,F

209 MA,l,ML***,p,l,F 829 LA02,LA08,LA08,p,LA08,F

210 a,L***,LA08,p,l,F 830 LA02,L***,L***,P,1,F

211 Ma,ML***,Ml,p,Ml,F 831 LA02,l,l,p,L***,F

212 A,Ml,Ml,p,Ml,F 832 A,L***,1,P,1,F

213 A,LA08,L***,P,M1,F 833 MA,1,LA08,P,L***,F

214 LA02,l,L***,p,ML***,F 834 a,l,L***,P,LA08,F

215 Ma,ML***,L***,P,l,F 835 Ma,l,LA08,P,LA08,F

216 BHF,L***,Ml,p,L***,F 836 LA02,L***,LA08,p,L***,F

217 LA02,L***,M1,P,M1,F 837 a,LA08,l,P,l,F

218 LA02,1,1,P,L***,F 838 Ma,l,ML***,p,L***,F

219 a,Ml,BHF,P,Ml,F 839 BHF,M1,M1,P,1,F

220 BHF,1,ML***,P,1,F 840 a,ML***,BHF,P,l,F

221 BHF,L***,l,p,l,F 841 BHF,Ml,l,p,ML***,F

222 A,1,M1,P,LA08,F 842 LA02,LA08,LA08,P,L***,F

223 A,M1,1,P,LA08,F 843 Ma,l,LA08,p,LA08,F

224 BHF,1,M1,P,M1,F 844 MA,LA08,LA08,P,LA08,F

225 MA,L***,M1,P,LA08,F 845 a,l,LA08,P,Ml,F

226 LA02,Ml,l,p,ML***,F 846 BHF,L***,M1,P,LA08,F

227 a,ML***,L***,P,Ml,F 847 A,l,l,p,ML***,F

228 A,M1,BHF,P,M1,F 848 MA,L***,L***,P,M1,F

229 Ma,LA08,l,P,l,F 849 Ma,LA08,BHF,p,ML***,F

230 LA02,ML***,ML***,p,Ml,F 850 LA02,Ml,BHF,p,Ml,F

231 a,l,l,P,L***,F 851 A,M1,BHF,P,1,F 232 A,ML***,1,P,LA08,F 852 A,ML***,l,p,L***,F

233 LA02,M1,ML***,P,M1,F 853 A,ML***,l,p,Ml,F

234 Ma,Ml,BHF,P,Ml,F 854 A,1,ML***,P,1,F

235 BHF,1,L***,P,ML***,F 855 a,Ml,BHF,p,Ml,F

236 A,1,ML***,P,ML***,F 856 MA,1,BHF,P,ML***,F

237 LA02,Ml,Ml,p,Ml,F 857 MA,M1,M1,P,M1,F

238 Ma,Ml,Ml,p,Ml,F 858 BHF,M1,M1,P,M1,F

239 BHF,L***,1,P,1,F 859 MA,Ml,l,p,L***,F

240 a,Ml,Ml,P,Ml,F 860 a,LA08,LA08,p,LA08,F

241 A,l,LA08,p,LA08,F 861 BHF,L***,BHF,P,ML***,F

242 A,L***,l,p,LA08,F 862 Ma,l,l,P,Ml,F

243 A,1,ML***,P,M1,F 863 BHF,ML***,LA08,p,Ml,F

244 A,ML***,LA08,P,M1,F 864 a,L***,L***,P,Ml,F

245 BHF,Ml,l,p,l,F 865 a,l,LA08,p,Ml,F

246 BHF,1,L***,P,L***,F 866 a,L***,l,p,l,F

247 LA02,M1,L***,P,M1,F 867 Ma,L***,LA08,p,LA08,F

248 BHF,L***,1,P,ML***,F 868 LA02,1,BHF,P,LA08,F

249 LA02,ML***,L***,P,1,F 869 LA02,l,l,p,Ml,F

250 A,1,ML***,P,LA08,F 870 A,L***,L***,P,1,F

251 A,M1,ML***,P,LA08,F 871 MA,L***,1,P,1,F

252 Ma,LA08,l,P,Ml,F 872 BHF,ML***,LA08,p,l,F

253 Ma,L***,LA08,P,ML***,F 873 A,ML***,1,P,1,F

254 LA02,M1,ML***,P,ML***,F 874 BHF,M1,M1,P,1,F

255 MA,l,L***,p,Ml,F 875 MA,ML***,L***,P,1,F

256 a,L***,Ml,p,ML***,F 876 a,LA08,ML***,p,LA08,F

257 A,Ml,LA08,p,ML***,F 877 LA02,ML***, L***,p,LA08,F

258 MA,l,Ml,p,l,F 878 a,Ml,LA08,P,l,F

259 LA02,L***,l,p,Ml,F 879 MA,Ml,BHF,p,l,F

260 Ma,l,L***,P,Ml,F 880 LA02,LA08,L***,p,ML***,F

261 BHF,l,ML***,p,l,F 881 A,Ml,l,p,L***,F

262 MA,L***,1,P,ML***,F 882 Ma,Ml,LA08,p,LA08,F

263 A,M1,1,P,M1,F 883 LA02,ML***, LA08,p,L***,F

264 A,L***,M1,P,LA08,F 884 a,Ml,l,p,l,F

265 a,Ml,l,P,LA08,F 885 MA,M1,L***,P,1,F

266 LA02,M1,M1,P,M1,F 886 LA02,M1,1,P,LA08,F

267 Ma,L***,LA08,P,Ml,F 887 Ma,l,BHF,P,L***,F

268 LA02,M1,LA08,P,LA08,F 888 A,L***,1,P,1,F

269 A,l,ML***,p,ML***,F 889 BHF,1,LA08,P,LA08,F

270 a,l,L***,p,Ml,F 890 Ma,l,BHF,p,Ml,F

271 LA02,Ml,BHF,p,Ml,F 891 Ma,l,BHF,P,LA08,F

272 BHF,M1,M1,P,M1,F 892 A,1,BHF,P,L***,F

273 MA,M1,M1,P,M1,F 893 BHF,M1,1,P,LA08,F

274 A,ML***, LA08,p,LA08,F 894 a,L***,Ml,p,L***,F

275 MA,1,M1,P,L***,F 895 MA,Ml,l,p,l,F 276 LA02,1,BHF,P,L***,F 896 BHF,M1,LA08,P,ML***,F

277 MA,M1,M1,P,M1,F 897 a,Ml,BHF,P,Ml,F

278 BHF,Up,l,F 898 a,Ml,BHF,p,LA08,F

279 BHF,Up,l,F 899 BHF,ML***,LA08,p,Ml,F

280 Ma,l,BHF,P,l,F 900 a,L***,l,P,LA08,F

281 A,ML***,l,p,LA08,F 901 a,Ml,LA08,p,L***,F

282 MA,l,ML***,p,ML***,F 902 LA02,L***,ML***,p,LA08,F

283 a,ML***,LA08,P,ML***,F 903 MA,LA08,BHF,p,l,F

284 BHF,L***,L***,p,Ml,F 904 BHF,LA08,LA08,P,1,F

285 A,M1,M1,P,M1,F 905 BHF,M1,L***,P,M1,F

286 A,M1,M1,P,M1,F 906 Ma,LA08,BHF,p,l,F

287 A,LA08,BHF,p,l,F 907 Ma,Ml,Ml,p,Ml,F

288 a,LA08,Ml,P,L***,F 908 BHF,LA08,M1,P,LA08,F

289 a,l,ML***,p,Ml,F 909 LA02,Ml,Ml,p,l,F

290 BHF,l,l,p,LA08,F 910 MA,ML***,l,p,LA08,F

291 LA02,1,LA08,P,M1,F 911 A,LA08,LA08,p,L***,F

292 a,LA08,Ml,P,L***,F 912 a,L***,l,P,l,F

293 LA02,Ml,ML***,p,l,F 913 BHF,LA08,BHF,P,1,F

294 MA,Ml,ML***,p,Ml,F 914 a,Ml,Ml,p,Ml,F

295 BHF,M1,L***,P,1,F 915 Ma,LA08,l,p,L***,F

296 BHF,M1,1,P,1,F 916 BHF,M1,ML***,P,M1,F

297 MA,LA08,ML***,p,l,F 917 A,1,1,P,1,F

298 a,Ml,L***,p,L***,F 918 a,ML***,l,P,l,F

299 A,M1,LA08,P,L***,F 919 MA,l,Ml,p,L***,F

300 A,1,LA08,P,L***,F 920 Ma,LA08,LA08,P,LA08,F

301 BHF,LA08,1,P,M1,F 921 a,l,Ml,p,l,F

302 Ma,ML***,Ml,P,LA08,F 922 Ma,l,l,P,LA08,F

303 BHF,LA08,L***,P,L***,F 923 LA02,Ml,BHF,p,Ml,F

304 LA02,Ml,BHF,p,Ml,F 924 Ma,L***,ML***,p,l,F

305 A,M1,M1,P,M1,F 925 MA,M1,M1,P,M1,F

306 BHF,l,LA08,p,l,F 926 A,Ml,l,p,l,F

307 A,M1,ML***,P,ML***,F 927 Ma,LA08,l,p,L***,F

308 MA,ML***,LA08,p,Ml,F 928 Ma,Ml,Ml,p,Ml,F

309 A,Ml,Ml,p,Ml,F 929 a,l,LA08,P,l,F

310 BHF,1,1,P,M1,F 930 LA02,ML***,BHF,p,Ml,F

311 MA,Ml,BHF,p,Ml,F 931 a,L***,LA08,P,l,F

312 BHF,1,L***,P,1,F 932 MA,ML***,BHF,P,1,F

313 MA,l,L***,p,l,F 933 MA,L***,1,P,LA08,F

314 BHF,l,BHF,p,Ml,F 934 a,Ml,Ml,p,l,F

315 a,Ml,l,P,Ml,F 935 LA02,ML***,BHF,p,LA08,F

316 BHF,l,BHF,p,l,F 936 LA02,L***,L***,p,l,F

317 A,M1,LA08,P,ML***,F 937 BHF,M1,LA08,P,ML***,F

318 a,l,L***,p,LA08,F 938 Ma,Ml,BHF,P,Ml,F

319 LA02,ML***,M1,P,1,F 939 a,l,L***,P,ML***,F 320 BHF,1,LA08,P,1,F 940 BHF,ML***,LA08,P,LA08,F

321 A,ML***,L***,p,l,F 941 A,U,p,l,F

322 MA,l,L***,p,LA08,F 942 MA,l,LA08,p,L***,F

323 BHF,Ml,L***,p,L***,F 943 a,l,Ml,P,Ml,F

324 A,LA08,L***,P,M1,F 944 MA,M1,L***,P,L***,F

325 A,Ml,LA08,p,Ml,F 945 Ma,l,l,p,ML***,F

326 LA02,Ml,Ml,p,Ml,F 946 Ma,l,BHF,p,Ml,F

327 A,Ml,L***,p,LA08,F 947 Ma,LA08,BHF,p,Ml,F

328 LA02,Ml,L***,p,l,F 948 MA,Ml,Ml,p,l,F

329 Ma,L***,l,P,Ml,F 949 A,l,l,p,Ml,F

330 A,LA08,1,P,LA08,F 950 a,Ml,LA08,p,Ml,F

331 LA02,Ml,l,p,Ml,F 951 MA,1,ML***,P,L***,F

332 A,Ml,BHF,p,Ml,F 952 a,L***,BHF,p,l,F

333 A,l,BHF,p,ML***,F 953 BHF,ML***,M1,P,LA08,F

334 LA02,ML***,Ml,p,Ml,F 954 a,l,l,P,LA08,F

335 LA02,l,L***,p,l,F 955 MA,1,1,P,M1,F

336 MA,Ml,LA08,p,ML***,F 956 BHF,ML***, LA08,P,LA08,F

337 LA02,ML***,M1,P,M1,F 957 MA,LA08,BHF,P,1,F

338 LA02,M1,BHF,P,M1,F 958 BHF,LA08,LA08,p,Ml,F

339 LA02,LA08,M1,P,1,F 959 A,1,BHF,P,M1,F

340 LA02,M1,M1,P,LA08,F 960 a,L***,Ml,p,Ml,F

341 LA02,ML***,LA08 ,p,Ml,F 961 MA,1,BHF,P,L***,F

342 Ma,LA08,Ml,p,l,F 962 BHF,L***,LA08,P,LA08,F

343 Ma,ML***,LA08,P,LA08,F 963 MA,L***,LA08,P,1,F

344 A,1,LA08,P,M1,F 964 BHF,Ml,LA08,p,l,F

345 a,ML***,Ml,P,LA08,F 965 a,l,Ml,p,ML***,F

346 LA02,ML***,1,P,1,F 966 Ma,Ml,BHF,p,LA08,F

347 MA,M1,LA08,P,LA08,F 967 BHF,ML*** LA08,p,ML***,F

348 BHF,1,L***,P,ML***,F 968 BHF,l,LA08,p,LA08,F

349 A,L***,M1,P,ML***,F 969 MA,1,1,P,L***,F

350 Ma,Ml,Ml,p,Ml,F 970 MA,M1,BHF,P,M1,F

351 Ma,Ml,L***,p,L***,F 971 MA,M1,LA08,P,1,F

352 a,LA08,Ml,p,Ml,F 972 a,LA08,l,p,l,F

353 a,ML***,LA08,p,Ml,F 973 MA,1,BHF,P,M1,F

354 A,M1,M1,P,LA08,F 974 MA,1,BHF,P,M1,F

355 Ma,LA08,l,p,ML***,F 975 a,ML***,l,p,ML***,F

356 BHF,l,L***,p,Ml,F 976 Ma,LA08,LA08,p,LA08,F

357 a,LA08,ML***,p,ML***,F 977 a,l,LA08,P,L***,F

358 A,Ml,ML***,p,LA08,F 978 a,L***,L***,p,l,F

359 BHF,1,L***,P,LA08,F 979 MA,LA08,LA08,p,LA08,F

360 BHF,M1,BHF,P,L***,F 980 BHF,ML***,LA08,P,M1,F

361 MA,M1,M1,P,M1,F 981 BHF,ML***,M1,P,M1,F

362 A,M1,1,P,L***,F 982 MA,l,BHF,p,L***,F

363 BHF,1,ML***,P,1,F 983 MA,l,L***,p,L***,F 364 Ma,Ml,ML***,p,Ml,F 984 BHF,LA08,L***,P,LA08,F

365 MA,1,ML***,P,1,F 985 BHF,1,LA08,P,LA08,F

366 LA02,L***,Ml,p,l,F 986 BHF,ML***,ML***,P,LA08,F

367 LA02,ML***,l,p,LA08,F 987 Ma,L***,BHF,P,L***,F

368 A,LA08,L***,P,LA08,F 988 BHF,LA08,BHF,P,M1,F

369 a,ML***,l,p,l,F 989 MA,M1,BHF,P,1,F

370 LA02,ML***,l,p,Ml,F 990 Ma,l,l,p,Ml,F

371 BHF,M1,BHF,P,1,F 991 a,L***,l,p,l,F

372 a,LA08,LA08,P,ML***,F 992 BHF,Ml,BHF,p,Ml,F

373 MA,M1,M1,P,M1,F 993 BHF,ML***, LA08,p,LA08,F

374 A,LA08,l,p,l,F 994 MA,l,l,p,LA08,F

375 MA,l,BHF,p,Ml,F 995 MA,LA08,L***,P,1,F

376 MA,M1,1,P,1,F 996 Ma,LA08,l,p,l,F

377 Ma,Ml,BHF,P,L***,F 997 BHF,LA08,LA08,p,L***,F

378 A,M1,M1,P,M1,F 998 Ma,L***,l,P,l,F

379 A,Ml,BHF,p,l,F 999 MA,Ml,Ml,p,l,F

380 LA02,l,LA08,p,Ml,F 1000 BHF,Ml,l,p,LA08,F

381 MA,1,ML***,P,M1,F 1001 Ma,Ml,Ml,P,l,F

382 BHF,L***,1,P,M1,F 1002 a,l,BHF,P,Ml,F

383 LA02,L***,LA08,P,M1,F 1003 Ma,L***,l,P,LA08,F

384 a,Ml,l,p,Ml,F 1004 MA,L***,l,p,LA08,F

385 Ma,l,LA08,p,Ml,F 1005 BHF,ML***,ML***,P,M1,F

386 MA,1,L***,P,ML***,F 1006 MA,LA08,L***,p,LA08,F

387 a,ML***,LA08,p,ML***,F 1007 BHF,ML***,LA08,p,Ml,F

388 BHF,ML***,LA08,P,M1,F 1008 MA,L***,BHF,p,l,F

389 A,ML***,1,P,M1,F 1009 a,l,l,p,l,F

390 Ma,ML***,l,P,LA08,F 1010 MA,L***,L***,p,l,F

391 a,l,BHF,p,ML***,F 1011 Ma,Ml,Ml,p,l,F

392 A,LA08,ML***,P,LA08,F 1012 MA,l,l,p,L***,F

393 a,l,ML***,p,LA08,F 1013 LA02,Ml,ML***,p,L***,F

394 Ma,l,LA08,P,LA08,F 1014 BHF,Ml,L***,p,Ml,F

395 Ma,Ml,L***,p,ML***,F 1015 Ma,L***,l,p,l,F

396 Ma,Ml,Ml,P,Ml,F 1016 a,l,l,P,Ml,F

397 A,LA08,M1,P,LA08,F 1017 BHF,LA08,LA08,p,Ml,F

398 BHF,1,1,P,1,F 1018 Ma,Ml,Ml,p,l,F

399 MA,l,LA08,p,ML***,F 1019 MA,1,L***,P,L***,F

400 Ma,L***,LA08,P,LA08,F 1020 Ma,L***,L***,P,l,F

401 LA02,L***,L***,p,Ml,F 1021 a,l,l,p,LA08,F

402 A,LA08,LA08,p,L***,F 1022 Ma,l,l,p,LA08,F

403 LA02,1,1,P,M1,F 1023 a,l,LA08,p,L***,F

404 Ma,Ml,LA08,p,ML***,F 1024 a,l,Ml,p,Ml,F

405 Ma,ML***,L***,p,LA08,F 1025 a,l,l,P,l,F

406 BHF,LA08,Ml,p,Ml,F 1026 LA02,LA08,BHF,p,Ml,F

407 BHF,l,L***,p,ML***,F 1027 BHF,LA08,BHF,P,LA08,F 408 MA,L***,BHF,p,L***,F 1028 BHF,ML***,BHF,P,LA08,F

409 LA02,Ml,Ml,p,Ml,F 1029 Ma,l,L***,p,L***,F

410 A,L***,1,P,LA08,F 1030 BHF,Ml,ML***,p,Ml,F

411 LA02,1,BHF,P,M1,F 1031 MA,M1,BHF,P,L***,F

412 a,ML***,ML***,P,LA08,F 1032 a,LA08,LA08,p,L***,F

413 A,1,L***,P,M1,F 1033 BHF,M1,BHF,P,LA08,F

414 MA,ML***,LA08,p,LA08,F 1034 a,L***,l,P,l,F

415 MA,l,Ml,p,LA08,F 1035 MA,1,1,P,LA08,F

416 A,l,LA08,p,ML***,F 1036 BHF,M1,LA08,P,LA08,F

417 Ma,l,ML***,p,l,F 1037 BHF,ML*** LA08,p,ML***,F

418 Ma,LA08,L***,p,Ml,F 1038 BHF,LA08,LA08,P,LA08,F

419 A,1,M1,P,M1,F 1039 BHF,LA08,L*** p,ML***, F

420 A,Ml,Ml,p,Ml,F 1040 a,l,l,P,l,F

421 a,ML***,l,P,ML***,F 1041 a,l,l,p,Ml,F

422 I_A02,L*** L***,P,LA08,F 1042 BHF,M1,BHF,P,ML***,F

423 MA,L***,L***,P,M1,F 1043 Ma,Ml,Ml,p,l,F

424 LA02,l,ML***,p,L***,F 1044 Ma,L***,l,p,L***,F

425 a,Ml,BHF,P,L***,F 1045 a,l,L***,p,L***,F

426 LA02,Ml,LA08,p,Ml,F 1046 BHF,LA08,BHF,p,Ml,F

427 BHF,LA08,1,P,L***,F 1047 Ma,L***,L***,p,l,F

428 A,L***,LA08,P,LA08,F 1048 a,L***,l,p,L***,F

429 A,Ml,LA08,p,Ml,F 1049 MA,L***,L***,P,1,F

430 BHF,Ml,Ml,p,Ml,F 1050 BHF,LA08,LA08,p,LA08,F

431 MA,1,LA08,P,M1,F 1051 MA,LA08,Ml,p,LA08,F

432 MA,LA08,L*** p,ML***,F 1052 Ma,Ml,BHF,p,Ml,F

433 a,L***,Ml,P,L***,F 1053 Ma,l,l,P,l,F

434 Ma,Ml,Ml,P,Ml,F 1054 MA,1,1,P,1,F

435 a,LA08,L***,P,L***,F 1055 MA,l,l,p,l,F

436 A,ML***,1,P,L***,F 1056 LA02,L*« L***,p,L***,F

437 MA,L***,1,P,M1,F 1057 BHF,LA08,BHF,p,LA08,F

438 LA02,1,ML***,P,LA08,F 1058 a,Ml,BHF,p,Ml,F

439 A,M1,M1,P,1,F 1059 LA02,M1,BHF,P,M1,F

440 MA,Ml,ML***,p,LA08,F 1060 BHF,ML*** BHF,p,ML***,F

441 MA,Ml,L***,p,LA08,F 1061 BHF,M1,BHF,P,M1,F

442 A,1,LA08,P,ML***,F 1062 a,Ml,BHF,p,Ml,F

443 a,LA08,l,P,L***,F 1063 BHF,Ml,BHF,p,Ml,F

444 LA02,LA08,ML***,P,M1,F 1064 BHF,Ml,BHF,p,Ml,F

445 MA,ML*** L***,p,LA08,F 1065 A,Ml,Ml,p,Ml,F

446 LA02,M1,ML***,P,1,F 1066 a,Ml,Ml,p,Ml,F

447 LA02,l,ML***,p,l,F 1067 A,M1,M1,P,M1,F

448 A,Ml,LA08,p,L***,F 1068 a,Ml,Ml,P,Ml,F

449 Ma,l,ML***,p,LA08,F 1069 MA,M1,M1,P,M1,F

450 MA,l,l,p,l,F 1070 Ma,Ml,Ml,P,Ml,F

451 A,Ml,L***,p,L***,F 1071 Ma,l,l,p,l,F 452 Ma,l,L***,P,ML***,F 1072 MA,l,l,p,l,F

453 a,LA08,L***,P,LA08,F 1073 MA,l,l,p,l,F

454 BHF,ML***,ML***,P,LA08,F 1074 Ma,Ml,BHF,P,Ml,F

455 LA02,LA08,l,p,L***,F 1075 a,l,l,p,l,F

456 LA02,LA08,M1,P,LA08,F 1076 MA,LA08,LA08,P,LA08,F

457 A,M1,M1,P,M1,F 1077 A,Ml,BHF,p,Ml,F

458 a,Ml,LA08,P,Ml,F 1078 MA,M1,BHF,P,M1,F

459 Ma,L***,LA08,p,Ml,F 1079 a,Ml,Ml,p,Ml,F

460 a,l,ML***,p,ML***,F 1080 BHF,1,1,P,M1,F

461 A,L*** I_A08,p,L***,F 1081 LA02,M1,BHF,P,ML***,F

462 LA02,Ml,LA08,p,Ml,F 1082 Ma,Ml,Ml,P,ML***,F

463 Ma,LA08,l,p,ML***,F 1083 LA02,ML***,BHF,p,Ml,F

464 a,Ml,Ml,P,Ml,F 1084 Ma,ML***,ML***,P,l,F

465 A,ML***,1,P,ML***,F 1085 MA,L***,LA08,P,LA08,F

466 MA,Ml,l,p,Ml,F 1086 Ma,L***,L***,p,ML***,F

467 Ma,l,L***,p,Ml,F 1087 MA,M1,M1,P,ML***,F

468 MA,LA08,ML*** p,ML***,F 1088 MA,M1,M1,P,ML***,F

469 LA02,1,BHF,P,L***,F 1089 Ma,L***,ML***,p,Ml,F

470 BHF,Ml,BHF,p,l,F 1090 MA,l,l,p,Ml,F

471 MA,1,L***,P,M1,F 1091 Ma,L*« L***,P,ML***,F

472 LA02,L***,ML***,p,Ml,F 1092 a,l,ML***,P,Ml,F

473 LA02,Ml,L***,p,Ml,F 1093 MA,1,1,P,ML***,F

474 LA02,l,L***,p,LA08,F 1094 A,LA08,BHF,p,L***,F

475 Ma,LA08,L***,p,ML***,F 1095 MA,M1,ML***,P,1,F

476 Ma,Ml,LA08,p,l,F 1096 LA02,ML***,ML***,P,LA08,F

477 LA02,Ml,LA08,p,LA08,F 1097 MA,l,l,p,ML***,F

478 MA,LA08,L***,p,L***,F 1098 BHF,l,ML***,p,ML***,F

479 LA02,LA08,L***,p,L***,F 1099 A,Ml,BHF,p,L***,F

480 BHF,1,ML***,P,ML***,F 1100 a,ML***,ML***,p,l,F

481 Ma,l,LA08,P,Ml,F 1101 Ma,Ml,ML***,p,L***,F

482 a,Ml,LA08,P,ML***,F 1102 MA,M1,LA08,P,M1,F

483 BHF,LA08,l,p,l,F 1103 Ma,L***,Ml,p,l,F

484 A,LA08,1,P,L***,F 1104 A,l,Ml,p,Ml,F

485 LA02,M1,L***,P,LA08,F 1105 Ma,ML***,LA08,p,l,F

486 A,L***,LA08,P,M1,F 1106 BHF,ML***,L***,p,Ml,F

487 A,l,l,p,l,F 1107 BHF,ML***,L***,p,Ml,F

488 LA02,Ml,LA08,p,Ml,F 1108 A,l,BHF,p,L***,F

489 LA02,Ml,BHF,p,l,F 1109 a,ML*** LA08,P,ML***, F

490 BHF,1,ML***,P,L***,F 1110 MA,L***,LA08,p,LA08,F

491 BHF,M1,BHF,P,M1,F 1111 a,ML***,ML***,p,l,F

492 BHF,ML***,LA08,P,1,F 1112 A,ML***,BHF,P,1,F

493 BHF,L***,BHF,P,L***,F 1113 MA,L***,l,p,l,F

494 a,LA08,BHF,P,l,F 1114 Ma,l,L***,p,ML***,F

495 MA,Ml,LA08,p,Ml,F 1115 BHF,ML***,L***,P,M1,F 496 BHF,1,LA08,P,L***,F 1116 Ma,l,l,p,L***,F

497 A,Ml,BHF,p,Ml,F 1117 BHF,ML***,L***,p,LA08,F

498 BHF,l,ML***,p,l,F 1118 Ma,L***,ML***,p,LA08,F

499 MA,LA08,1,P,1,F 1119 MA,M1,M1,P,1,F

500 LA02,ML***,l,p,l,F 1120 Ma,Ml,LA08,p,L***,F

501 A,1,L***,P,ML***,F 1121 A,ML***,BHF,P,LA08,F

502 Ma,Ml,Ml,P,Ml,F 1122 BHF,ML***,L***,P,LA08,F

503 MA,Ml,LA08,p,ML***,F 1123 BHF,Ml,L***,p,LA08,F

504 BHF,Ml,BHF,p,Ml,F 1124 LA02,ML***, L***,P,LA08,F

505 LA02,LA08,L***,P,ML***,F 1125 a,l,l,p,ML***,F

506 a,ML***,LA08,P,l,F 1126 MA,1,BHF,P,LA08,F

507 LA02,Ml,LA08,p,l,F 1127 BHF,ML***, LA08,p,LA08,F

508 A,ML***,BHF,p,l,F 1128 Ma,Ml,Ml,P,ML***,F

509 LA02,ML***,ML***,p,l,F 1129 LA02,L***,L***,p,LA08,F

510 A,l,ML***,p,L***,F 1130 Ma,Ml,l,p,Ml,F

511 A,l,L***,p,ML***,F 1131 MA,Ml,ML***,p,Ml,F

512 a,ML***,L***,p,Ml,F 1132 MA,ML***,ML***,P,1,F

513 Ma,ML***,LA08,p,LA08,F 1133 a,l,l,p,L***,F

514 A,ML***,M1,P,1,F 1134 a,ML***,BHF,p,LA08,F

515 LA02,M1,ML***,P,LA08,F 1135 Ma,ML***,LA08,p,Ml,F

516 LA02,LA08,1,P,1,F 1136 LA02,M1,1,P,M1,F

517 LA02,1,M1,P,1,F 1137 a,Ml,l,p,L***,F

518 LA02,1,M1,P,1,F 1138 a,ML***,l,p,L***,F

519 BHF,M1,BHF,P,1,F 1139 a,l,l,P,ML***,F

520 LA02,Ml,LA08,p,LA08,F 1140 Ma,l,L***,P,L***,F

521 LA02,ML***,Ml,p,l,F 1141 a,L***,ML***,P,Ml,F

522 LA02,l,LA08,p,ML***,F 1142 a,Ml,Ml,P,l,F

523 MA,M1,L***,P,ML***,F 1143 BHF,ML*** L***,p,L***,F

524 A,1,LA08,P,1,F 1144 BHF,ML*** LA08,p,ML***,F

525 A,LA08,M1,P,M1,F 1145 A,ML***,BHF,p,LA08,F

526 a,Ml,L***,P,l,F 1146 MA,L***,l,p,LA08,F

527 a,Ml,ML***,p,LA08,F 1147 BHF,LA08,BHF,p,L***,F

528 LA02,l,l,p,ML***,F 1148 a,l,Ml,P,Ml,F

529 A,1,1,P,LA08,F 1149 A,l,l,p,L***,F

530 Ma,l,L***,p,LA08,F 1150 BHF,Ml,LA08,p,Ml,F

531 LA02,LA08,M1,P,1,F 1151 a,ML***,BHF,P,L***,F

532 A,Ml,ML***,p,L***,F 1152 Ma,L***,BHF,p,l,F

533 Ma,l,L***,p,l,F 1153 Ma,Ml,l,p,Ml,F

534 MA,Ml,ML***,p,L***,F 1154 BHF,ML*** L***,p,LA08,F

535 LA02,l,ML***,p,ML***,F 1155 a,l,BHF,P,L***,F

536 LA02,Ml,Ml,p,Ml,F 1156 BHF,M1,M1,P,LA08,F

537 I_A02,L***, LA08,P,LA08,F 1157 Ma,ML***,L***,P,L***,F

538 MA,Ml,Ml,p,Ml,F 1158 LA02,LA08,BHF,P,ML***,F

539 LA02,M1,LA08,P,ML***,F 1159 MA,ML*** L***,p,L***, F 540 LA02,LA08,l,p,l,F 1160 BHF,L***,BHF,p,L***,F

541 LA02,LA08,l,p,Ml,F 1161 Ma,L***,BHF,p,L***,F

542 a,ML***,L***,P,l,F 1162 A,M1,LA08,P,1,F

543 Ma,L***,Ml,p,LA08,F 1163 Ma,ML***,BHF,P,LA08,F

544 Ma,L***,L***,P,Ml,F 1164 a,l,Ml,p,LA08,F

545 MA,1,LA08,P,M1,F 1165 A,L***,L***,P,LA08,F

546 BHF,LA08,Ml,p,l,F 1166 Ma,ML***,L***,p,L***,F

547 A,LA08,LA08,P,LA08,F 1167 BHF,l,ML***,p,LA08,F

548 a,LA08,BHF,P,L***,F 1168 MA,L***,BHF,p,L***,F

549 LA02,Ml,L***,p,LA08,F 1169 A,ML***,L***,p,ML***,F

550 A,LA08,ML***,P,LA08,F 1170 A,L***,Ml,p,l,F

551 Ma,Ml,LA08,P,LA08,F 1171 MA,ML***,l,p,L***,F

552 a,LA08,Ml,P,LA08,F 1172 a,l,Ml,p,Ml,F

553 BHF,LA08,M1,P,L***,F 1173 BHF,Ml,BHF,p,l,F

554 a,Ml,l,p,LA08,F 1174 LA02,L***,BHF,p,L***,F

555 Ma,Ml,ML***,p,LA08,F 1175 a,l,Ml,P,ML***,F

556 A,LA08,M1,P,1,F 1176 MA,M1,M1,P,1,F

557 A,L***, L***,P,LA08,F 1177 BHF,Ml,ML***,p,LA08,F

558 LA02,ML***,BHF,p,l,F 1178 BHF,ML*** LA08,p,L***, F

559 a,Ml,BHF,P,ML***,F 1179 BHF,ML*** LA08,p,L***, F

560 BHF,l,BHF,p,LA08,F 1180 A,l,Ml,p,L***,F

561 MA,1,1,P,1,F 1181 A,1,ML***,P,L***,F

562 BHF,M1,L***,P,ML***,F 1182 A,M1,M1,P,1,F

563 BHF,l,BHF,p,ML***,F 1183 LA02,l,LA08,p,l,F

564 A,LA08,BHF,P,L***,F 1184 Ma,ML***,l,p,ML***,F

565 a,ML***,Ml,p,LA08,F 1185 a,l,Ml,p,L***,F

566 LA02,ML***,L***,p,Ml,F 1186 LA02,M1,LA08,P,LA08,F

567 Ma,L***,ML***,P,l,F 1187 A,LA08,L***,p,L***,F

568 LA02,ML***,l,p,L***,F 1188 Ma,L***,LA08,p,ML***,F

569 A,LA08,LA08,p,LA08,F 1189 Ma,L***,BHF,p,LA08,F

570 BHF,L***,M1,P,1,F 1190 MA,M1,1,P,L***,F

571 MA,Ml,Ml,p,Ml,F 1191 A,L***,l,p,l,F

572 BHF,ML***,l,p,Ml,F 1192 a,L***,ML***,P,l,F

573 MA,l,ML***,p,L***,F 1193 BHF,ML***,BHF,p,LA08,F

574 A,ML***, LA08,p,LA08,F 1194 BHF,L***,LA08,p,l,F

575 A,L***,L***,P,M1,F 1195 Ma,l,LA08,P,L***,F

576 MA,1,1,P,M1,F 1196 A,L***,ML***,p,l,F

577 MA,l,BHF,p,l,F 1197 MA,L***,LA08,p,L***,F

578 a,LA08,Ml,P,l,F 1198 a,ML***,BHF,p,Ml,F

579 MA,1,L***,P,LA08,F 1199 a,Ml,LA08,P,Ml,F

580 a,Ml,L***,p,LA08,F 1200 BHF,L***,M1,P,LA08,F

581 BHF,M1,L***,P,L***,F 1201 MA,l,LA08,p,l,F

582 LA02,M1,BHF,P,M1,F 1202 LA02,ML***,BHF,P,L***,F

583 LA02,l,LA08,p,L***,F 1203 BHF,M1,LA08,P,1,F 584 a,L***,Ml,P,ML***,F 1204 A,Ml,LA08,p,LA08,F

585 BHF,LA08,L***,p,l,F 1205 BHF,Ml,L***,p,ML***,F

586 Ma,Ml,LA08,P,LA08,F 1206 Ma,l,LA08,p,L***,F

587 BHF,L***,L***,P,M1,F 1207 BHF,Ml,LA08,p,ML***,F

588 BHF,l,LA08,p,Ml,F 1208 MA,L***,LA08,P,LA08,F

589 BHF,l,L***,p,LA08,F 1209 a,Ml,BHF,p,LA08,F

590 A,1,ML***,P,1,F 1210 MA,L***,BHF,P,1,F

591 BHF,l,L***,p,LA08,F 1211 MA,LA08,BHF,P,L***,F

592 A,LA08,L***,P,LA08,F 1212 a,ML***,LA08,p,LA08,F

593 LA02,LA08,Ml,p,LA08,F 1213 MA,LA08,BHF,p,L***,F

594 a,Ml,BHF,p,ML***,F 1214 A,l,L***,p,L***,F

595 I_A02,L*** L***,p,LA08,F 1215 a,LA08,ML***,p,ML***,F

596 Ma,Ml,L***,p,LA08,F 1216 Ma,Ml,LA08,P,l,F

597 BHF,l,L***,p,l,F 1217 a,l,ML***,p,L***,F

598 MA,LA08,Ml,p,l,F 1218 BHF,M1,M1,P,ML***,F

599 LA02,Ml,LA08,p,ML***,F 1219 Ma,ML***,LA08,P,l,F

600 A,l,Ml,p,ML***,F 1220 Ma,l,BHF,p,ML***,F

601 BHF,M1,L***,P,M1,F 1221 BHF,Ml,Ml,p,LA08,F

602 A,LA08,M1,P,LA08,F 1222 Ma,Ml,BHF,p,l,F

603 a,LA08,l,p,ML***,F 1223 MA,Ml,BHF,p,l,F

604 Ma,l,l,P,l,F 1224 LA02,LA08,M1,P,M1,F

605 Ma,Ml,Ml,p,Ml,F 1225 MA,ML***,LA08,P,1,F

606 Ma,l,BHF,P,ML***,F 1226 MA,LA08,ML***,P,1,F

607 Ma,l,L***,P,l,F 1227 Ma,LA08,L***,p,Ml,F

608 MA,ML***,L***,p,l,F 1228 a,LA08,Ml,p,L***,F

609 A,LA08,l,p,L***,F 1229 a,LA08,l,P,ML***,F

610 a,L***,Ml,P,LA08,F 1230 A,LA08,Ml,p,ML***,F

611 LA02,LA08,BHF,P,M1,F 1231 a,LA08,L***,p,l,F

612 a,ML***,l,p,LA08,F 1232 MA,LA08,L***,p,l,F

613 LA02,LA08,Ml,p,Ml,F 1233 a,LA08,LA08,p,L***,F

614 MA,l,LA08,p,Ml,F 1234 LA02,LA08,L***,p,LA08,F

615 LA02,M1,BHF,P,M1,F 1235 MA,LA08,LA08,P,L***,F

616 LA02,M1,L***,P,LA08,F 1236 a,LA08,LA08,p,L***,F

617 a,Ml,BHF,p,l,F 1237 a,LA08,LA08,p,L***,F

618 LA02,LA08,BHF,P,1,F 1238 A,l,Ml,p,Ml,F

619 LA02,Ml,Ml,p,Ml,F 1239 BHF,l,Ml,p,l,F

620 BHF,1,BHF,P,ML***,F 1240 Ma,Ml,Ml,P,ML***,F

PHARMACEUTICAL COMPOSITIONS AND METHODS OF USE

The pharmaceutical composition according to the embodiments can further comprise a pharmaceutically acceptable carrier. The composition is conveniently formulated in a form suitable for oral (including buccal and sublingual) administration, for example as a tablet, capsule, thin film, powder, suspension, solution, syrup, dispersion or emulsion. The composition can contain components conventional in pharmaceutical preparations, e.g. one or more carriers, binders, lubricants, excipients, pH modifiers, sweeteners, bulking agents, coloring agents or further active agents.

As described above, patients can be humans, and also other mammals, such as livestock, zoo animals and companion animals, such as a cat, dog or horse.

In some embodiments, the present disclosure provides cyclic peptide scaffolds for use in the treatment of a patient.

In another aspect, the embodiments provide a method of treating a patient requiring treatment, which comprises administering an effective amount of one or more of the cyclic peptide scaffolds or pharmaceutical composition as described hereinabove. The amount of the one or more of the cyclic peptide scaffolds or pharmaceutical composition disclosed herein to be administered to a patient to be effective will depend upon the bioavailability of the particular composition, as well as other factors, such as the species, age, weight, sex, and condition of the patient, manner of administration and judgment of the prescribing physician. In general, the composition dose can be such that the cyclic peptide is in the range of from 0.01 milligrams per kilogram to 20 milligrams per kilogram (mg/kg) body weight. For example, a composition comprising a cyclic peptide scaffold compound can be administered at a dose equivalent to administration in the range of from 0.02 to 0.5 mg/kg body weight or 0.01 mg/kg to 10 mg/kg body weight or 0.01 to 2 mg/kg body weight.

The present disclosure also provides dose units of the subject cyclic peptide scaffold compounds that can provide for a desired pharmacokinetic (PK) profile. Dose units can provide a modified PK profile compared to a reference PK profile as disclosed herein. It will be appreciated that a modified PK profile can provide for a modified pharmacodynamic (PD) profile. Ingestion of multiples of such a dose unit can also provide a desired PK profile. The term dose unit is used herein to refer to a composition that provdies a therapeutically effective amount of drug (i.e., a sufficient amount of drug to effect a therapeutic effect, e.g., a dose within the respective drug's therapeutic window, or therapeutic range). "Multiple dose units" or "multiples of a dose unit" or a "multiple of a dose unit" refers to at least two single dose units.

As used herein, a "PK profile" refers to a profile of drug concentration in blood or plasma. Such a profile can be a relationship of drug concentration over time (i.e., a

"concentration-time PK profile") or a relationship of drug concentration versus number of doses ingested (i.e., a "concentration-dose PK profile".) A PK profile is characterized by PK parameters.

As used herein, a "PK parameter" refers to a measure of drug concentration in blood or plasma, such as: 1) "drug Cmax", the maximum concentration of drug achieved in blood or plasma; 2) "drug Tmax", the time elapsed following ingestion to achieve Cmax; and 3) "drug exposure", the total concentration of drug present in blood or plasma over a selected period of time, which can be measured using the area under the curve (AUC) of a time course of drug release over a selected period of time (t). Modification of one or more PK parameters provides for a modified PK profile.

For purposes of describing the features of dose units of the present disclosure, "PK parameter values" that define a PK profile include drug Cmax (e.g., phenolic opioid Cmax), total drug exposure (e.g., area under the curve) and l/(drug Tmax) (such that a decreased 1/Tmax is indicative of a delay in Tmax relative to a reference Tmax) . Thus a decrease in a PK parameter value relative to a reference PK parameter value can indicate, for example, a decrease in drug Cmax, a decrease in drug exposure, and/or a delayed Tmax.

Dose units of the present disclosure can be adapted to provide for a modified PK profile, e.g., a PK profile that is different from that achieved from dosing a given dose of the cyclic peptide scaffold compound. For example, dose units can provide for at least one of decreased drug Cmax, delayed drug Tmax and/or decreased drug exposure.

As used herein, "a pharmacodynamic (PD) profile" refers to a profile of the efficacy of a drug in a patient (or subject or user), which is characterized by PD parameters. "PD parameters" include "drug Emax" (the maximum drug efficacy), "drug EC50" (the concentration of drug at 50% of the Emax), and side effects.

A dose unit can be adapted to provide for a desired PK profile (e.g., a concentration-time PK profile) following ingestion of a single dose. A dose unit can be adapted to provide for a desired PK profile (e.g., a concentration-dose PK profile) following ingestion of multiple dose units (e.g., at least 2, at least 3, at least 4 or more dose units).

In compositions of the present disclosure, the compounds disclosed herein may be administered in the form of their pharmaceutically acceptable salts, or they may also be used alone or in appropriate association, as well as in combination, with other pharmaceutically active compounds. The following methods and excipients are merely exemplary and are in no way limiting. The cyclic peptide scaffold compounds can be administered to a host using any available conventional methods and routes suitable for delivery of conventional drugs, including systemic or localized routes. In general, routes of administration contemplated include but are not necessarily limited to, enteral, parenteral, or inhalational routes, such as intrapulmonary or intranasal delivery.

Conventional and pharmaceutically acceptable routes of administration include intranasal, intrapulmonary, intramuscular, intratracheal, subcutaneous, intradermal, topical application, intravenous, rectal, nasal, oral and other parenteral routes of administration. Routes of administration may be combined, if desired, or adjusted depending upon the agent and/or the desired effect. The composition can be administered in a single dose or in multiple doses.

For oral preparations, the subject compounds can be used alone or in combination with appropriate additives to make tablets, powders, granules or capsules, for example, with conventional additives, such as lactose, mannitol, corn starch or potato starch; with binders, such as crystalline cellulose, cellulose derivatives, acacia, corn starch or gelatins; with disintegrators, such as corn starch, potato starch or sodium carboxymethylcellulose; with lubricants, such as talc or magnesium stearate; and if desired, with diluents, buffering agents, moistening agents, preservatives and flavoring agents. If oral administration is desired, the subject compounds may optionally be provided in a composition that protects it from the acidic environment of the stomach. For example, the composition can be formulated in an enteric coating that maintains its integrity in the stomach and releases the active compound in the intestine. The composition may also be formulated in combination with an antacid or other such ingredient.

Parenteral routes of administration other than inhalation administration include, but are not necessarily limited to, topical, transdermal, subcutaneous, intramuscular, intraorbital, intracapsular, intraspinal, intrasternal, and intravenous routes. Parenteral administration can be carried to effect systemic or local delivery of the agent. Where systemic delivery is desired, administration typically involves invasive or systemically absorbed topical or mucosal administration of pharmaceutical preparations. Where local delivery is desired, administration typically involves administering the composition to a desired target tissue, such a liver, heart, spine, etc. For local delivery, the administration may be by injection or by placement of the composition in the desired tissue or organ by surgery, for example.

Methods of administration of the agent through the skin or mucosa include, but are not necessarily limited to, topical application of a suitable pharmaceutical preparation, transdermal transmission, injection and epidermal administration. For transdermal transmission, absorption promoters or iontophoresis are suitable methods. Iontophoretic transmission may be

accomplished using commercially available "patches" which deliver their product continuously via electric pulses through unbroken skin for periods of several days or more.

The subject compounds of the invention can be formulated into preparations for injection by dissolving, suspending or emulsifying them in an aqueous or nonaqueous solvent, such as vegetable or other similar oils, synthetic aliphatic acid glycerides, esters of higher aliphatic acids or propylene glycol; and if desired, with conventional additives such as solubilizers, isotonic agents, suspending agents, emulsifying agents, stabilizers and preservatives.

The subject compounds can also be delivered to the subject by enteral administration. Enteral routes of administration include, but are not necessarily limited to, oral and rectal (e.g., using a suppository) delivery.

Furthermore, the subject compounds can be made into suppositories by mixing with a variety of bases such as emulsifying bases or water-soluble bases. The compounds of the present invention can be administered rectally via a suppository. The suppository can include vehicles such as cocoa butter, carbowaxes and polyethylene glycols, which melt at body temperature, yet are solidified at room temperature.

Aspects of the present disclosure also include a library having 5 or more of the cell permeable cyclic peptide scaffolds described hereinabove, such as 10 or more, such as 15 or more, such as 20 or more, such as 25 or more, such as 30 or more, such as 35 or more, such as 40 or more, such as 45 or more, such as 50 or more, such as 75 or more and including a library having 100 or more of the subject cell permeable cyclic peptide scaffolds. The library of compounds may be include cyclic peptide scaffolds having similar amino acid sequences, conformation structures, or cell permeability values as desired. In embodiments, libraries of interest include 5 or more cell permeable cyclic peptide scaffolds, eaching having a structure according to Formula I:

Cyclo [Z-Y-X-Pro-Y-Phe] Formula I

wherein:

Pro is L-proline or D-proline;

Phe is L-phenylalanine or D-phenylalanine;

each Ri is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl, or optionally, R ¹ together with the atoms to which it is bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring;

each R ₂ is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl, or optionally, R ¹ together with the atoms to which it is bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring;

each R ₃ is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl, or optionally, R ¹ together with the atoms to which it is bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring;

A is selected from -NR _a -, -O- or -S-;

B is selected from -NR _t ,-, -O- or -S-;

C is selected from -NR _C -, -O- or -S-;

each R _a , R _b , R _c is independently selected from hydrogen, alkyl, substituted alkyl, aryl and substituted aryl, or

Ri and R _a together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring; R ₂ and ¾ together with the atoms to which they are bonded form a

cycloheteroalkyl or substituted cycloheteroalkyl ring;

R3 and R _c together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring;

n is an integer from one to 5 and a is an integer from one to 5;

p is an integer from one to 5 and b is an integer from one to 5; and

r is an integer from one to 5 and c is an integer from one to 5 ;

or a pharmaceutical acceptable salt, solvate or hydrate thereof.

EXAMPLES

As can be appreciated from the disclosure provided above, the present disclosure has a wide variety of applications. Accordingly, the following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the present invention, and are not intended to limit the scope of what the inventors regard as their invention nor are they intended to represent that the experiments below are all or the only experiments performed. Those of skill in the art will readily recognize a variety of noncritical parameters that could be changed or modified to yield essentially similar results. Thus, the following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the present invention, and are not intended to limit the scope of what the inventors regard as their invention nor are they intended to represent that the experiments below are all or the only experiments performed. Efforts have been made to ensure accuracy with respect to numbers used (e.g. amounts, dimensions, etc.) but some experimental errors and deviations should be accounted for.

General

All starting reagents were commercially available and used without further purification except where mentioned. Purification was performed on a Biotage Isolera Prime HPLC using various solvent systems and columns (listed individually). Composition and purity were tested by HPLC (Waters 1525) with an attached mass spectrometer (Micromass ZQ, waters) and PDA detector (Waters 2998) through a 3.5 μιη C18 column (XBridge BEH C18 4.6 x 50 mm). A mixture of water (0.1% formic acid) and ACN (0.1% formic acid) was used as an eluent, with results being analyzed by MassLynx4.1. Runs were 12 minutes long with 1.2 ml/min flow rate; ACN concentration was increased stepwise from its starting concentration (30% 0-2 min, linear increase to 100% 2-10 min, 100% 10-12 min). Tandem MS runs and LC-MS analyses for PAMPA were performed on an UHPLC (UltiMate 3000, Dionex) with attached mass spectrometer (Orbitrap Velos Pro, Thermo Scientific) through a 2.2 μιη CI 8 column (Acclaim 120 2.1 x 250 mm, Thermo Scientific). A mixture of water (0.1% formic acid) and ACN (0.1% formic acid) was used as an eluent, with results being analyzed by XCALIBUR version 2.2 SP1.48. Runs were 32.7 minutes long with 0.5 ml/min flow rate; ACN concentration was increased stepwise from its starting concentration (40% 0-2 min, linear increase to 85% 2-22 min, 100% 22-27 min, 40% 27-32.7 min).

Fmoc addition to isotopically labeled leucine

Fmoc was added to unprotected isotopically labeled leucine. The procedure used herein was adapted from Malkov A et al, Journal of Organic Chemistry 74, 5839-5849, 2009 (including supporting information) which incorporated by reference herein. One gram of isotopically labeled leucine was added to a separate flask containing 30ml of distilled water 80% saturated with sodium bicarbonate, then agitated by sonication until dissolved. 2.82g (1 molar equivalent) of Fmoc succinimide was added to a separate round-bottom flask in an ice bath containing 30ml dioxane. The dissolved leucine was added dropwise to the Fmoc solution over 10 minutes with rapid stirring. The mixture was stirred 2 hours on ice, then allowed to come to room temperature overnight with continued stirring. The mixture was then evaporated at 25 degrees Celsius and brought up in a minimal volume of DMF before reverse-phase purification over a SNAP Ultra C18 30g cartridge (Biotage), eluting with water (0.1% TFA)/ACN (0.1% TFA). The resulting fractions were analyzed on the Waters LC-MS system, pooled, and evaporated to a white solid.

N-methylation of Fmoc amino acids

All N-methylated amino acids used in the library synthesis were synthesized via the following procedure: Fmoc amino acid and paraformaldehyde (1:1 by mass) were added to a round-bottom flask containing 75ml toluene per 5g of amino acid. The flask was heated to 90 degrees Celsius before 0.2 molar equivalents of camphorsulfonic acid was added. The flask was stirred for at least 2 hours, then the solution was evaporated to 3ml volume per gram of amino acid. 5ml of ethyl acetate per gram of amino acid was added. The solution was then transferred to a separatory funnel and washed twice with an equal volume of water saturated with sodium bicarbonate and once with an equal volume of brine. The organic layer was dried with magnesium sulfate, filtered into a round-bottom flask, then evaporated to a minimal volume. 2ml of DCM per gram of amino acid was added to the flask and the oil or solid thoroughly dissolved. Once dissolved, an equal volume of trifluoroacetic acid was added, then stirred for 5 minutes. Finally, 3 molar equivalents of triethylsilane was added and let stir overnight. The solution was then evaporated to minimal volume before addition of 5ml ethyl acetate per gram of amino acid, transferred to a separatory funnel and washed twice with an equal volume of distilled water and once with an equal volume of brine. The organic layer was dried, filtered into a round-bottom flask, and evaporated to a white solid, then analyzed for purity.

Cyclic peptomer synthesis

Linear peptomers were synthesized on 2-chlorotrityl resin (0.14 mmol/g) using extended Fmoc coupling (Fmoc amino acid/HATU/DIPEA in DMF, overnight) and peptoid synthesis conditions (bromoacetic acid/DIC in DMF, lhr, then amine in DMF, overnight). The linear peptomers were cleaved from resin with 30% HFIP in DCM. Cyclization was performed in dilute conditions (<3 mM peptomer in a solution of 1: 1 ACN:THF) with COMU (2 equiv) and DIPEA (10 equiv) and stirred overnight at room temperature. Each sublibrary was briefly purified using Isolute 103 SPE cartridge (200 mg/6 mL, Biotage).

Resin loading procedure

Phenylalanine and 2-Chlorotrityl resin were placed in a vacuum desiccator with phosphorous pentoxide overnight. The phenylalanine was added to a flame-dried round-bottom flask. Dry DCM of sufficient volume for the resin to float freely and 4 molar equivalents of dry DIPEA was added to the flask, which was then sonicated until the phenylalanine dissolved completely. The resin was added to the flask and the flask purged of air with a flow of argon, after which the flask was agitated for 4hrs. The resin was transferred to a solid-phase synthesis tube/manifold and washed with 2 resin-volumes of DMF (3x), then 2 resin- volumes DCM (3x), always keeping the solvent level above the resin. Finally, the resin was capped with a solution of 17:2: 1 DCM :MeOH: DIPEA (2 resin-volumes, 3x, 15min incubation each). Loading value was calculated via resin cleavage (1% TFA) followed by quantification by UV absorbance at 280nm.

Fmoc deprotection

Two resin-volumes of 2% DBU 2% piperidine in DMF was added to the resin and the tube was capped and agitated for 20 minutes. The resin was then drained and washed with 2 resin- volumes of DMF (x3) and 2 resin- volumes of DCM (x3). Amino Acid Couplings

Due to low resin loading value, 12 molar equivalents of Fmoc amino acid, 11.4 molar equivalents of HATU, and 15 molar equivalents of DIPEA were used to maintain high concentration in a DMF volume large enough to cover the resin. Fmoc amino acid, HATU, and dipea were added to a vial, then solubilized in the minimal amount of DMF which covers the resin- volume. The vial was set aside to react for 15 minutes before its contents were added to the resin. The SPPS tube was then capped and agitated overnight. The resin was then drained and washed with 2 resin- volumes of DMF (x3) and 2 resin-volumes of DCM (x3).

Peptoid Synthesis

For the same reasons as above, the 30 molar equivalents of bromoacetic acid was added to a vial and solubilized in a minimal volume of DMF which still covers the resin volume. 18 molar equivalents of DIC was then added, and the vial capped, mixed, and reacted for 15 minutes. The vial's contents were then added to the resin. The SPPS tube was then capped and agitated for 1 hour, after which the resin was drained and washed as above. 30 molar equivalents of the amine of choice was then added directly to the resin and the volume was increased with a minimal amount of DMF before capping the tube and agitating overnight (although the extended reaction time likely had little bearing on the results!). Finally, the resin was drained and washed as above.

Peptide cleavage

Two resin-volumes of 30% HFIP in DCM was added to the resin, the tube capped, then agitated for 30 minutes. The tube was then drained into a vial, and was further washed with an equal volume of DCM three times. This above was then repeated with the addition of a further wash step of an equal volume of acetone. The contents of the vial were then evaporated.

Peptide cyclization

5ml ACN and 10 molar equivalents of DIPEA were added to each vial containing a cleaved sublibrary. The vials were then sonicated until all peptides were totally dissolved before addition of 5ml THF, diluting the peptides to <3mM. 2 molar equivalents of COMU were added to each vial, all of which were stirred overnight. Finally, each vial was evaporated to a solid or oil. Purification of sublibraries

Purification of each sublibrary was performed on individual Isolute 103 ENV+ flash chromatography columns (200mg/6ml). Each sublibrary was dissolved in a minimal volume of DMF (75ul or less) and loaded onto the dry column. The column was washed with 10ml of water, followed by elution with 10ml of methanol into tared vials. The methanol was then evaporated and the vials weighed for final yield.

Verification of Synthesis

The composition and purity of each sublibrary were tested by LC-MS (Waters system). Expected UV absorbance and masses for the library and possible truncations were observed to verify synthesis and purity.

MSMS and PAMPA LC-MS data acquisition

PAMPA LC-MS data was acquired as above with no modifications. Tandem MS data was acquired by taking the 5 most intense non-isotopic peaks (Xcalibur setting) for MS2 acquisition at every MS 1 acquisition.

Parallel Artificial Membrane Permeability Assay procedure

Parallel Artificial Membrane Permeability Assay (PAMPA) was performed with a 96- well filter donor plate with 0.45 μιη hydrophobic Immobilon-P membrane supports (Millipore) and a 96-well teflon acceptor plate. The donor plate filter was loaded with 5 μΐ, οί 1% lecithin in n-dodecane. lNMe3, a well-characterized cyclic peptide, was added as a standard in each well at a concentration of lOuM. 150ul of each sublibrary (including standard) in PBS (containing 5% DMSO) was loaded into the donor plate (300uM theoretical concentration, or ~2uM per compound). The acceptor plate was loaded with 300ul of PBS with 5% DMSO. The donor filter plate was then loaded into the acceptor plate and was left in a damp chamber at 25 °C for 18 hours. The concentration of each compound in the donor and acceptor wells was quantified by LC-MS to calculate Pe.

PAMPA Data Analysis

For each well, single ion chromatograms for each library mass were extracted, followed by peak-finding by first differential. The peak boundaries were found by following outward from peaks until the second differential met a detection threshold at a point sufficiently below the intensity of the peak center-point. Peaks and peak boundaries which were incorrectly detected were manually corrected. Integration was performed by fitting a Gaussian distribution to each peak and calculating its area.

Peaks were matched by retention time and peak number across wells to get acceptor and donor well intensities for each peak. A time independent permeability value was then calculated via the following equations:

C _D x V _D + C _A x V _A

r '- ^■ eq =

V _D + V _A

%T = x 100

c, eq

Wherein C is concentration, V is well volume, %T is percent transmittance to the acceptor well, and Pe is the desired time-independent permeability value. The subscript eq stands for equilibrium, A for acceptor and D for donor. For these calculations, concentration has been substituted for intensity under the peak since the ionization intensity of a compound should not vary overly much between two wells. Finally, the Pe values were corrected based on the known Pe of the lNMe3 standard.

Permeability values for the compounds of Table 1 were determined as described above and are summarized in Table 2.

Permeability

Compound Value

No. Peptomer Sequence (x 10 ^"6 cm/s)

1 BHF,L***,BHF,p,L***,F 56.19061214

2 BHF,l,Ml,p,Ml,F 50.8282355

3 A,L***,L***,p,LA08,F 48.71672758

4 BHF,l,Ml,p,l,F 46.22198458

5 BHF,L***,1,P,L***,F 42.78148279

6 Ma,Ml,L***,P,l,F 41.14185131

7 A,L***,l,p,l,F 36.44199332

8 A,M1,BHF,P,1,F 34.07095274

9 A,Ml,l,p,ML***,F 33.27688014

10 a,Ml,l,P,Ml,F 32.88796918

11 MA,M1,M1,P,M1,F 32.57897584

12 A,l,BHF,p,l,F 30.68291478 13 BHF,1,M1,P,M1,F 29.1942956

14 MA,M1,M1,P,ML***,F 28.52497238

15 MA,LA08,M1,P,1,F 28.50650176

16 MA,M1,L***,P,M1,F 28.33829512

17 BHF,1,ML* * *,P,ML* * *,F 27.98815431

18 BHF,L***,BHF,p,l,F 27.68606544

19 MA,LA08,L***,P,M1,F 27.41715714

20 BHF,M1,M1,P,M1,F 27.07177771

21 LA02,1,M1,P,M1,F 26.82931976

22 a,Ml,ML***,p,l,F 26.82301824

23 a,L***,L***,p,Ml,F 26.76564435

24 BHF,Ml,Ml,p,Ml,F 26.70634473

25 BHF,M1,M1,P,M1,F 26.55043548

26 Ma,L***,ML***,P,Ml,F 26.50654657

27 MA,ML***,LA08,P,LA08,F 26.32870586

28 MA,M1,M1,P,M1,F 26.22773297

29 BHF,Ml,Ml,p,l,F 26.17265039

30 a,ML***,L***,p,l,F 26.1105021

31 Ma,Ml,L***,P,ML***,F 25.94258816

32 A,Ml,Ml,p,l,F 25.80002884

33 A,Ml,L***,p,Ml,F 25.78220373

34 A,LA08,Ml,p,L***,F 25.55775971

35 A,M1,L***,P,M1,F 25.36713829

36 a,Ml,BHF,p,Ml,F 25.35607442

37 Ma,ML***,l,P,ML***,F 25.10086123

38 A,M1,M1,P,ML***,F 25.09089699

39 MA,1,M1,P,ML***,F 25.0861927

40 A,Ml,Ml,p,LA08,F 25.03162272

41 MA,M1,ML***,P,M1,F 25.01886329

42 BHF,M1,M1,P,M1,F 24.87040135

43 Ma,Ml,l,P,Ml,F 24.82810692

44 Ma,Ml,l,P,Ml,F 24.82810692

45 LA02,M1,LA08,P,M1,F 24.5926188

46 LA02,M1,LA08,P,M1,F 24.5926188

47 A,L***,BHF,p,l,F 24.57015331

48 MA,M1,M1,P,L***,F 24.38438951

49 Ma,Ml,Ml,P,Ml,F 24.38348673

50 Ma,ML***,Ml,P,Ml,F 24.31080278

51 MA,1,M1,P,1,F 24.17124034

52 A,M1,ML***,P,M1,F 24.16377896

53 A,L***,Ml,p,ML***,F 24.16030909

54 MA,L***,M1,P,M1,F 23.92605054

55 A,l,LA08,p,l,F 23.91283292 56 Ma,Ml,ML***,P,Ml,F 23.73833678

57 MA,M1,LA08,P,ML***,F 23.72007441

58 A,M1,BHF,P,M1,F 23.59143159

59 BHF,l,l,p,Ml,F 23.53463022

60 a,L***,BHF,p,l,F 23.26495371

61 a,L***,LA08,P,L***,F 23.22930206

62 BHF,L***,l,p,Ml,F 23.10492023

63 a,Ml,L***,p,Ml,F 23.0837236

64 MA,ML***,M1,P,M1,F 22.86097011

65 Ma,l,ML***,P,ML***,F 22.72909836

66 BHF,Ml,Ml,p,Ml,F 22.65698306

67 MA,ML***,L***,p,Ml,F 22.65481294

68 a,ML***,Ml,P,l,F 22.58524245

69 A,Ml,Ml,p,Ml,F 22.48095643

70 A,ML***,BHF,P,L***,F 22.47943243

71 A,L***,L***,p,l,F 22.35705255

72 Ma,ML***,Ml,P,L***,F 22.21408662

73 A,l,ML***,p,l,F 22.16308149

74 A,Ml,BHF,p,Ml,F 22.04952601

75 MA,1,M1,P,LA08,F 21.9422274

76 A,Ml,BHF,p,Ml,F 21.89615654

77 LA02,M1,BHF,P,L***,F 21.85502465

78 A,Ml,l,p,LA08,F 21.78328972

79 A,Ml,l,p,Ml,F 21.65504441

80 A,Ml,L***,p,ML***,F 21.64904102

81 Ma,Ml,L***,P,LA08,F 21.58462332

82 A,l,Ml,p,Ml,F 21.47967737

83 a,Ml,L***,P,Ml,F 21.43740026

84 MA,Ml,Ml,p,Ml,F 21.43183575

85 A,L***,LA08,p,Ml,F 21.40673824

86 MA,L***,M1,P,M1,F 21.2633048

87 MA,M1,M1,P,LA08,F 21.25660811

88 LA02,M1,L***,P,1,F 21.21198624

89 Ma,L***,Ml,P,ML***,F 21.1569649

90 Ma,ML***,L***,P,Ml,F 20.98978613

91 A,M1,BHF,P,M1,F 20.9628871

92 Ma,Ml,Ml,P,Ml,F 20.76313119

93 a,Ml,BHF,p,Ml,F 20.74335994

94 BHF,M1,M1,P,M1,F 20.73949965

95 a,Ml,L***,P,ML***,F 20.73281225

96 BHF,L***,LA08,P,L***,F 20.72754175

97 A,Ml,L***,p,l,F 20.51626729

98 LA02,M1,BHF,P,M1,F 20.41552774

99 A,M1,L***,P,ML***,F 20.2928769 100 MA,ML***,1,P,M1,F 20.24070307

101 Ma,Ml,Ml,P,Ml,F 20.2032426

102 a,Ml,BHF,p,Ml,F 20.10606447

103 LA02,M1,M1,P,M1,F 20.05269969

104 MA,M1,ML* * *,P,LA08,F 19.92606853

105 LA02,L***,1,P,L***,F 19.78870101

106 MA,l,L***,p,ML***,F 19.73554909

107 Ma,L***,Ml,p,ML***,F 19.73186827

108 MA,M1,1,P,ML***,F 19.69291384

109 MA,L***,M1,P,ML* * *,F 19.6567569

110 BHF,L***,M1,P,L***,F 19.61804884

111 Ma,ML***,Ml,P,LA08,F 19.53234979

112 a,LA08,Ml,p,L***,F 19.52903752

113 LA02,1,M1,P,M1,F 19.51724784

114 A,L***,LA08,p,l,F 19.5156128

115 a,ML***,Ml,P,LA08,F 19.49874601

116 a,l,LA08,p,l,F 19.49562529

117 a,Ml,LA08,p,l,F 19.47372828

118 19.46627882

119 LA02,Ml,Ml,p,Ml,F 19.45529183

120 A,l,L***,p,L***,F 19.36475021

121 LA02,M1,1,P,1,F 19.28813728

122 a,Ml,BHF,P,Ml,F 19.25184441

123 A,L***,LA08,p,LA08,F 19.22735011

124 A,l,L***,p,Ml,F 19.15078912

125 a,Ml,L***,p,l,F 19.11174655

126 Ma,Ml,BHF,P,Ml,F 19.08802734

127 Ma,Ml,l,P,LA08,F 19.04687727

128 MA,1,ML* * *,P,ML* * *,F 18.99987845

129 BHF,Ml,Ml,p,Ml,F 18.94392122

130 Ma,Ml,l,P,l,F 18.93627832

131 Ma,LA08,Ml,P,L***,F 18.91178744

132 Ma,L***,Ml,P,L***,F 18.89699421

133 a,Ml,l,P,ML***,F 18.86867707

134 BHF,1,M1,P,1,F 18.8550913

135 BHF,l,L***,p,ML***,F 18.84710992

136 a,Ml,LA08,p,ML***,F 18.80246438

137 MA,1,M1,P,M1,F 18.79110041

138 MA,M1,1,P,M1,F 18.79110041

139 BHF,M1,M1,P,M1,F 18.77564569

140 A,L***,M1,P,L***,F 18.76412648

141 a,Ml,L***,p,ML***,F 18.75454855

142 MA,L***,M1,P,1,F 18.72629726

143 LA02,M1,1,P,M1,F 18.57443693 144 Ma,LA08,l,P,Ml,F 18.56149677

145 MA,M1,BHF,P,M1,F 18.49316068

146 BHF,1,1,P,ML***,F 18.45259647

147 Ma,L***,l,P,ML***,F 18.32419316

148 Ma,L***,l,P,L***,F 18.30172016

149 MA,1,LA08,P,ML***,F 18.26363562

150 BHF,Ml,Ml,p,Ml,F 18.22781209

151 MA,M1,1,P,M1,F 18.20517238

152 MA,M1,1,P,M1,F 18.20517238

153 LA02,L***,L***,P,M1,F 18.18720053

154 a,LA08,Ml,P,Ml,F 18.15357743

155 MA,M1,M1,P,1,F 17.98832753

156 MA,M1,M1,P,1,F 17.98832753

157 Ma,l,Ml,P,Ml,F 17.98816681

158 LA02,l,L***,p,Ml,F 17.98540374

159 Ma,LA08,Ml,P,Ml,F 17.9484773

160 LA02,1,L***,P,ML***,F 17.8677765

161 A,l,ML***,p,Ml,F 17.83963166

162 Ma,Ml,BHF,P,Ml,F 17.82220647

163 a,LA08,ML***,P,Ml,F 17.80862671

164 LA02,L***,1,P,M1,F 17.79963046

165 Ma,Ml,BHF,P,Ml,F 17.7337768

166 A,Ml,Ml,p,Ml,F 17.72766039

167 a,ML***,L***,p,ML***,F 17.70135387

168 LA02,M1,M1,P,M1,F 17.67238466

169 A,Ml,ML***,p,L***,F 17.66551964

170 MA,1,1,P,LA08,F 17.65724109

171 a,Ml,L***,P,LA08,F 17.62447466

172 A,L***,ML***,p,Ml,F 17.6142183

173 BHF,l,Ml,p,L***,F 17.57956415

174 a,LA08,Ml,p,ML***,F 17.5486073

175 MA,ML***,LA08,P,LA08,F 17.54234433

176 BHF,ML***,LA08,p,ML***,F 17.51418039

177 BHF,L***,Ml,p,l,F 17.49544027

178 LA02,1,ML***,P,M1,F 17.46829141

179 Ma,ML***,L***,p,Ml,F 17.40797742

180 MA,1,ML***,P,LA08,F 17.3559126

181 A,ML***,M1,P,M1,F 17.31337854

182 Ma,l,ML***,P,l,F 17.30863947

183 BHF,L***,l,p,LA08,F 17.30227074

184 LA02,L***,l,p,ML***,F 17.28279029

185 LA02,ML***,l,p,ML***,F 17.10834035

186 Ma,l,ML***,p,ML***,F 17.09109135

187 MA,Ml,L***,p,ML***,F 17.04239744 188 LA02,M1,BHF,P,M1,F 17.00852323

189 LA02,ML***,l,p,LA08,F 16.98977471

190 MA,l,LA08,p,ML***,F 16.93095047

191 Ma,L***,Ml,P,LA08,F 16.9245817

192 Ma,Ml,Ml,P,l,F 16.8735617

193 A,L***,BHF,P,ML***,F 16.86530105

194 a,Ml,l,p,ML***,F 16.85433362

195 A,M1,M1,P,L***,F 16.84945047

196 a,Ml,Ml,P,l,F 16.83154675

197 A,Ml,ML***,p,l,F 16.79150455

198 Ma,L***,Ml,P,l,F 16.7716384

199 A,L***,L***,p,Ml,F 16.7279933

200 A,1,L***,P,LA08,F 16.71717023

201 A,ML***,M1,P,ML* * *,F 16.71659758

202 LA02,M1,M1,P,1,F 16.71497558

203 BHF,Ml,Ml,p,Ml,F 16.61938228

204 LA02,Ml,Ml,p,Ml,F 16.61477747

205 LA02,M1,M1,P,M1,F 16.53444871

206 LA02,1,L***,P,1,F 16.51415444

207 a,Ml,Ml,p,Ml,F 16.50115041

208 a,LA08,ML* * *,P,ML* * *,F 16.47863675

209 MA,l,ML***,p,l,F 16.47315765

210 a,L***,LA08,p,l,F 16.47314921

211 Ma,ML***,Ml,p,Ml,F 16.41152869

212 A,Ml,Ml,p,Ml,F 16.40602598

213 A,LA08,L***,P,M1,F 16.38356976

214 LA02,l,L***,p,ML***,F 16.37435754

215 Ma,ML***,L***,P,l,F 16.35782285

216 BHF,L***,Ml,p,L***,F 16.30049653

217 LA02,L***,M1,P,M1,F 16.25446901

218 LA02,1,1,P,L***,F 16.24185622

219 a,Ml,BHF,P,Ml,F 16.22333019

220 BHF,1,ML***,P,1,F 16.2199749

221 BHF,L***,l,p,l,F 16.21290967

222 A,1,M1,P,LA08,F 16.13438796

223 A,M1,1,P,LA08,F 16.13150772

224 BHF,1,M1,P,M1,F 16.11552468

225 MA,L***,M1,P,LA08,F 16.11353439

226 LA02,Ml,l,p,ML***,F 16.06160444

227 a,ML***,L***,P,Ml,F 16.03460499

228 A,M1,BHF,P,M1,F 15.99903862

229 Ma,LA08,l,P,l,F 15.97290745

230 LA02,ML***,ML* * *,p,Ml,F 15.96856352

231 a,l,l,P,L***,F 15.95794462 232 A,ML***,1,P,LA08,F 15.93909991

233 LA02,M1,ML* * *,P,M1,F 15.9017328

234 Ma,Ml,BHF,P,Ml,F 15.86578743

235 BHF,1,L* * *,P,ML** *,F 15.79262297

236 A,1,ML***,P,ML***,F 15.71564676

237 LA02,Ml,Ml,p,Ml,F 15.70403365

238 Ma,Ml,Ml,p,Ml,F 15.69511476

239 BHF,L***,1,P,1,F 15.69315428

240 a,Ml,Ml,P,Ml,F 15.63313769

241 A,l,LA08,p,LA08,F 15.58997604

242 A,L***,l,p,LA08,F 15.56273971

243 A,1,ML***,P,M1,F 15.54088864

244 A,ML***,LA08,P,M1,F 15.53169555

245 BHF,Ml,l,p,l,F 15.5025513

246 BHF,1,L***,P,L***,F 15.5017172

247 LA02,M1,L***,P,M1,F 15.49541105

248 BHF,L***,1,P,ML***,F 15.4724259

249 LA02,ML***,L***,P,1,F 15.43740559

250 A,1,ML***,P,LA08,F 15.41168385

251 A,M1,ML***,P,LA08,F 15.38459523

252 Ma,LA08,l,P,Ml,F 15.38085543

253 Ma,L***,LA08,P,ML***,F 15.37105241

254 LA02,M1,ML* * *,P,ML* **,F 15.21410223

255 MA,l,L***,p,Ml,F 15.19253259

256 a,L***,Ml,p,ML***,F 15.15432076

257 A,Ml,LA08,p,ML***,F 15.06505249

258 MA,l,Ml,p,l,F 15.04796558

259 LA02,L***,l,p,Ml,F 15.03779291

260 Ma,l,L***,P,Ml,F 15.03506168

261 BHF,l,ML***,p,l,F 15.02224354

262 MA,L***,1,P,ML***,F 15.00436914

263 A,M1,1,P,M1,F 14.98102179

264 A,L***,M1,P,LA08,F 14.89646656

265 a,Ml,l,P,LA08,F 14.89615672

266 LA02,M1,M1,P,M1,F 14.88908064

267 Ma,L***,LA08,P,Ml,F 14.78884386

268 LA02,M1,LA08,P,LA08,F 14.71448863

269 A,l,ML***,p,ML***,F 14.68900781

270 a,l,L***,p,Ml,F 14.61652756

271 LA02,Ml,BHF,p,Ml,F 14.60273571

272 BHF,M1,M1,P,M1,F 14.59898542

273 MA,M1,M1,P,M1,F 14.59463904

274 A,ML***,LA08,p,LA08,F 14.58763062

275 MA,1,M1,P,L***,F 14.57290574 276 LA02,1,BHF,P,L***,F 14.54063724

277 MA,M1,M1,P,M1,F 14.53241073

278 BHF,l,l,p,l,F 14.53035014

279 BHF,l,l,p,l,F 14.53035014

280 Ma,l,BHF,P,l,F 14.51066215

281 A,ML***,l,p,LA08,F 14.49020071

282 MA,l,ML***,p,ML***,F 14.47722646

283 a,ML***,LA08,P,ML***,F 14.47295475

284 BHF,L***,L***,p,Ml,F 14.46686498

285 A,M1,M1,P,M1,F 14.41367424

286 A,M1,M1,P,M1,F 14.41367424

287 A,LA08,BHF,p,l,F 14.37489535

288 a,LA08,Ml,P,L***,F 14.3588776

289 a,l,ML***,p,Ml,F 14.34321989

290 BHF,l,l,p,LA08,F 14.32015491

291 LA02,1,LA08,P,M1,F 14.31637679

292 a,LA08,Ml,P,L***,F 14.28954986

293 LA02,Ml,ML***,p,l,F 14.25635378

294 MA,Ml,ML***,p,Ml,F 14.25599002

295 BHF,M1,L***,P,1,F 14.25275906

296 BHF,M1,1,P,1,F 14.23889246

297 MA,LA08,ML***,p,l,F 14.23396924

298 a,Ml,L***,p,L***,F 14.16251831

299 A,M1,LA08,P,L***,F 14.15268194

300 A,1,LA08,P,L***,F 14.07794459

301 BHF,LA08,1,P,M1,F 14.00927789

302 Ma,ML***,Ml,P,LA08,F 13.98383886

303 BHF,LA08,L* * *,P,L** *,F 13.96167677

304 LA02,Ml,BHF,p,Ml,F 13.94351241

305 A,M1,M1,P,M1,F 13.93909716

306 BHF,l,LA08,p,l,F 13.92082944

307 A,M1,ML* * *,P,ML* * *,F 13.85607019

308 MA,ML***,LA08,p,Ml,F 13.8343356

309 A,Ml,Ml,p,Ml,F 13.81799304

310 BHF,1,1,P,M1,F 13.80170138

311 MA,Ml,BHF,p,Ml,F 13.78906142

312 BHF,1,L***,P,1,F 13.77226775

313 MA,l,L***,p,l,F 13.74395145

314 BHF,l,BHF,p,Ml,F 13.73456859

315 a,Ml,l,P,Ml,F 13.71285744

316 BHF,l,BHF,p,l,F 13.69640691

317 A,M1,LA08,P,ML***,F 13.68166075

318 a,l,L***,p,LA08,F 13.64865683

319 LA02,ML***,M1,P,1,F 13.62670989 320 BHF,1,LA08,P,1,F 13.60501049

321 A,ML***,L***,p,l,F 13.59271209

322 MA,l,L***,p,LA08,F 13.57036188

323 BHF,Ml,L***,p,L***,F 13.56602015

324 A,LA08,L***,P,M1,F 13.54743987

325 A,Ml,LA08,p,Ml,F 13.53244538

326 LA02,Ml,Ml,p,Ml,F 13.51585557

327 A,Ml,L***,p,LA08,F 13.51368794

328 LA02,Ml,L***,p,l,F 13.51085873

329 Ma,L***,l,P,Ml,F 13.47557403

330 A,LA08,1,P,LA08,F 13.46652765

331 LA02,Ml,l,p,Ml,F 13.46651411

332 A,Ml,BHF,p,Ml,F 13.46034782

333 A,l,BHF,p,ML***,F 13.42999756

334 LA02,ML***,Ml,p,Ml,F 13.41658601

335 LA02,l,L***,p,l,F 13.38203284

336 MA,Ml,LA08,p,ML***,F 13.37827685

337 LA02,ML* * * ,M1,P,M1,F 13.35044535

338 LA02,M1,BHF,P,M1,F 13.32074194

339 LA02,LA08,M1,P,1,F 13.27845085

340 LA02,M1,M1,P,LA08,F 13.27788945

341 LA02,ML* * * ,LA08 ,p,Ml,F 13.26225567

342 Ma,LA08,Ml,p,l,F 13.24549565

343 Ma,ML***,LA08,P,LA08,F 13.23173168

344 A,1,LA08,P,M1,F 13.22457132

345 a,ML***,Ml,P,LA08,F 13.21467684

346 LA02,ML***,1,P,1,F 13.17537765

347 MA,M1,LA08,P,LA08,F 13.16825196

348 BHF,1,L* * *,P,ML** *,F 13.1671722

349 A,L***,M1,P,ML***,F 13.16677535

350 Ma,Ml,Ml,p,Ml,F 13.15497613

351 Ma,Ml,L***,p,L***,F 13.15137152

352 a,LA08,Ml,p,Ml,F 13.13765997

353 a,ML***,LA08,p,Ml,F 13.11783791

354 A,M1,M1,P,LA08,F 13.0552946

355 Ma,LA08,l,p,ML***,F 13.05294248

356 BHF,l,L***,p,Ml,F 13.02817814

357 a,LA08,ML***,p,ML***,F 12.99665604

358 A,Ml,ML***,p,LA08,F 12.98699884

359 BHF,1,L***,P,LA08,F 12.97614593

360 BHF,M1,BHF,P,L***,F 12.96211767

361 MA,M1,M1,P,M1,F 12.86418892

362 A,M1,1,P,L***,F 12.83953132

363 BHF,1,ML***,P,1,F 12.83540366 364 Ma,Ml,ML***,p,Ml,F 12.82155693

365 MA,1,ML***,P,1,F 12.78167723

366 LA02,L***,Ml,p,l,F 12.77806535

367 LA02,ML***,l,p,LA08,F 12.76568836

368 A,LA08,L***,P,LA08,F 12.75886886

369 a,ML***,l,p,l,F 12.74944654

370 LA02,ML***,l,p,Ml,F 12.72752444

371 BHF,M1,BHF,P,1,F 12.60378433

372 a,LA08,LA08,P,ML* * *,F 12.59939348

373 MA,M1,M1,P,M1,F 12.54321102

374 A,LA08,l,p,l,F 12.48129444

375 MA,l,BHF,p,Ml,F 12.47101605

376 MA,M1,1,P,1,F 12.40018963

377 Ma,Ml,BHF,P,L***,F 12.36119896

378 A,M1,M1,P,M1,F 12.35053235

379 A,Ml,BHF,p,l,F 12.34098032

380 LA02,l,LA08,p,Ml,F 12.33153725

381 MA,1,ML***,P,M1,F 12.32844411

382 BHF,L***,1,P,M1,F 12.29193608

383 LA02,L***,LA08,P,M1,F 12.29073611

384 a,Ml,l,p,Ml,F 12.25785791

385 Ma,l,LA08,p,Ml,F 12.22560074

386 MA,1,L***,P,ML***,F 12.21173435

387 a,ML***,LA08,p,ML***,F 12.20097919

388 BHF,ML***,LA08,P,M1,F 12.16312141

389 A,ML***,1,P,M1,F 12.13945126

390 Ma,ML***,l,P,LA08,F 12.05950752

391 a,l,BHF,p,ML***,F 12.02350374

392 A,LA08,ML***,P,LA08,F 12.02339437

393 a,l,ML***,p,LA08,F 11.98988226

394 Ma,l,LA08,P,LA08,F 11.97735999

395 Ma,Ml,L***,p,ML***,F 11.97433204

396 Ma,Ml,Ml,P,Ml,F 11.95760508

397 A,LA08,M1,P,LA08,F 11.94247557

398 BHF,1,1,P,1,F 11.93620769

399 MA,l,LA08,p,ML***,F 11.91440886

400 Ma,L***,LA08,P,LA08,F 11.90580391

401 LA02,L***,L***,p,Ml,F 11.89457829

402 A,LA08,LA08,p,L***,F 11.8916768

403 LA02,1,1,P,M1,F 11.89148268

404 Ma,Ml,LA08,p,ML* * *,F 11.87951487

405 Ma,ML***,L***,p,LA08,F 11.8657429

406 BHF,LA08,Ml,p,Ml,F 11.86354209

407 BHF,l,L***,p,ML***,F 11.8465143 408 MA,L***,BHF,p,L***,F 11.81568914

409 LA02,Ml,Ml,p,Ml,F 11.81300096

410 A,L***,1,P,LA08,F 11.80634988

411 LA02,1,BHF,P,M1,F 11.78306695

412 a,ML***,ML***,P,LA08,F 11.76930838

413 A,1,L***,P,M1,F 11.75739516

414 MA,ML***,LA08,p,LA08,F 11.75012842

415 MA,l,Ml,p,LA08,F 11.7066321

416 A,l,LA08,p,ML***,F 11.69139032

417 Ma,l,ML***,p,l,F 11.69018972

418 Ma,LA08,L***,p,Ml,F 11.68097375

419 A,1,M1,P,M1,F 11.67215488

420 A,Ml,Ml,p,Ml,F 11.6708824

421 a,ML***,l,P,ML***,F 11.62755806

422 LA02,L***,L***,P,LA08,F 11.60051198

423 MA,L***,L***,P,M1,F 11.58242904

424 LA02,l,ML***,p,L***,F 11.53970127

425 a,Ml,BHF,P,L***,F 11.53741255

426 LA02,Ml,LA08,p,Ml,F 11.50816966

427 BHF,LA08,1,P,L***,F 11.49086837

428 A,L***,LA08,P,LA08,F 11.46140752

429 A,Ml,LA08,p,Ml,F 11.45827993

430 BHF,Ml,Ml,p,Ml,F 11.43468181

431 MA,1,LA08,P,M1,F 11.41533436

432 MA,LA08,L* **,p,ML* * *,F 11.39463489

433 a,L***,Ml,P,L***,F 11.38840445

434 Ma,Ml,Ml,P,Ml,F 11.38484272

435 a,LA08,L***,P,L***,F 11.37202846

436 A,ML***,1,P,L***,F 11.34763032

437 MA,L***,1,P,M1,F 11.3403253

438 LA02,1,ML* * *,P,LA08,F 11.31935215

439 A,M1,M1,P,1,F 11.31550664

440 MA,M1,ML* * *,p,LA08,F 11.31270331

441 MA,Ml,L***,p,LA08,F 11.26658443

442 A,1,LA08,P,ML***,F 11.25340711

443 a,LA08,l,P,L***,F 11.24073126

444 LA02,LA08,ML* * *,P,M1,F 11.2240681

445 MA,ML* * *,L* * *,p,LA08,F 11.21773269

446 LA02,M1,ML***,P,1,F 11.2038765

447 LA02,l,ML***,p,l,F 11.19139945

448 A,Ml,LA08,p,L***,F 11.17294641

449 Ma,l,ML***,p,LA08,F 11.17154455

450 MA,l,l,p,l,F 11.15483763

451 A,Ml,L***,p,L***,F 11.15384133 452 Ma,l,L***,P,ML***,F 11.14084235

453 a,LA08,L***,P,LA08,F 11.13170381

454 BHF,ML***,ML***,P,LA08,F 11.1300007

455 LA02,LA08,l,p,L***,F 11.12077509

456 LA02,LA08,M1,P,LA08,F 11.11239467

457 A,M1,M1,P,M1,F 11.10605987

458 a,Ml,LA08,P,Ml,F 11.08040848

459 Ma,L***,LA08,p,Ml,F 11.06700862

460 a,l,ML***,p,ML***,F 11.05716762

461 A,L***,LA08,p,L***,F 11.04762588

462 LA02,Ml,LA08,p,Ml,F 11.01911964

463 Ma,LA08,l,p,ML***,F 11.00753821

464 a,Ml,Ml,P,Ml,F 10.99483912

465 A,ML***,1,P,ML***,F 10.99059111

466 MA,Ml,l,p,Ml,F 10.98389537

467 Ma,l,L***,p,Ml,F 10.96931203

468 MA,LA08,ML***,p,ML***,F 10.95272724

469 LA02,1,BHF,P,L***,F 10.94048337

470 BHF,Ml,BHF,p,l,F 10.90683173

471 MA,1,L***,P,M1,F 10.89476174

472 LA02,L* * * ,ML* * *,p,Ml,F 10.85672407

473 LA02,Ml,L***,p,Ml,F 10.81739315

474 LA02,l,L***,p,LA08,F 10.81720781

475 Ma,LA08,L***,p,ML***,F 10.81173878

476 Ma,Ml,LA08,p,l,F 10.80968441

477 LA02,Ml,LA08,p,LA08,F 10.8082134

478 MA,LA08,L***,p,L***,F 10.80759226

479 LA02,LA08,L** *,p,L* * *,F 10.76342435

480 BHF,1,ML* * *,P,ML* * *,F 10.74069253

481 Ma,l,LA08,P,Ml,F 10.67978794

482 a,Ml,LA08,P,ML***,F 10.66489775

483 BHF,LA08,l,p,l,F 10.65589664

484 A,LA08,1,P,L***,F 10.64954297

485 LA02,M1,L***,P,LA08,F 10.64731224

486 A,L***,LA08,P,M1,F 10.61764419

487 A,l,l,p,l,F 10.616968

488 LA02,Ml,LA08,p,Ml,F 10.61411526

489 LA02,Ml,BHF,p,l,F 10.61411526

490 BHF,1,ML* * *,P,L** *,F 10.61055238

491 BHF,M1,BHF,P,M1,F 10.60337842

492 BHF,ML***,LA08,P,1,F 10.59249394

493 BHF,L***,BHF,P,L***,F 10.58270593

494 a,LA08,BHF,P,l,F 10.56527141

495 MA,Ml,LA08,p,Ml,F 10.54209193 496 BHF,1,LA08,P,L***,F 10.52391316

497 A,Ml,BHF,p,Ml,F 10.49832262

498 BHF,l,ML***,p,l,F 10.48610492

499 MA,LA08,1,P,1,F 10.47587086

500 LA02,ML***,l,p,l,F 10.47248244

501 A,1,L***,P,ML***,F 10.4452417

502 Ma,Ml,Ml,P,Ml,F 10.44310076

503 MA,Ml,LA08,p,ML***,F 10.38960721

504 BHF,Ml,BHF,p,Ml,F 10.38811427

505 LA02,LA08,L***,P,ML***,F 10.38303635

506 a,ML***,LA08,P,l,F 10.38125717

507 LA02,Ml,LA08,p,l,F 10.35501938

508 A,ML***,BHF,p,l,F 10.34392486

509 LA02,ML***,ML* * *,p,l,F 10.33568023

510 A,l,ML***,p,L***,F 10.31645393

511 A,l,L***,p,ML***,F 10.30829187

512 a,ML***,L***,p,Ml,F 10.30294089

513 Ma,ML***,LA08,p,LA08,F 10.30260088

514 A,ML***,M1,P,1,F 10.29020859

515 LA02,M1,ML* * *,P,LA08,F 10.23700271

516 LA02,LA08,1,P,1,F 10.22478091

517 LA02,1,M1,P,1,F 10.19247245

518 LA02,1,M1,P,1,F 10.19247245

519 BHF,M1,BHF,P,1,F 10.0880796

520 LA02,Ml,LA08,p,LA08,F 9.987721562

521 LA02,ML***,Ml,p,l,F 9.985820738

522 LA02,l,LA08,p,ML* * *,F 9.975015248

523 MA,M1,L* * *,P,ML* * *,F 9.964912872

524 A,1,LA08,P,1,F 9.962388042

525 A,LA08,M1,P,M1,F 9.952205367

526 a,Ml,L***,P,l,F 9.855274575

527 a,Ml,ML***,p,LA08,F 9.839043457

528 LA02,l,l,p,ML***,F 9.825155355

529 A,1,1,P,LA08,F 9.812290975

530 Ma,l,L***,p,LA08,F 9.778237191

531 LA02,LA08,M1,P,1,F 9.77761088

532 A,Ml,ML***,p,L***,F 9.770813193

533 Ma,l,L***,p,l,F 9.764531664

534 MA,Ml,ML***,p,L***,F 9.750745143

535 LA02,1,ML* * *,p,ML** *,F 9.739676705

536 LA02,Ml,Ml,p,Ml,F 9.72873097

537 LA02,L***,LA08,P,LA08,F 9.720623957

538 MA,Ml,Ml,p,Ml,F 9.688707921

539 LA02,M1,LA08,P,ML* * *,F 9.672273612 540 LA02,LA08,l,p,l,F 9.632201764

541 LA02,LA08,l,p,Ml,F 9.631578926

542 a,ML***,L***,P,l,F 9.610381805

543 Ma,L***,Ml,p,LA08,F 9.598223554

544 Ma,L***,L***,P,Ml,F 9.576568139

545 MA,1,LA08,P,M1,F 9.569340747

546 BHF,LA08,Ml,p,l,F 9.565372495

547 A,LA08,LA08,P,LA08,F 9.558499572

548 a,LA08,BHF,P,L***,F 9.513743034

549 LA02,Ml,L***,p,LA08,F 9.454798609

550 A,LA08,ML***,P,LA08,F 9.450444361

551 Ma,Ml,LA08,P,LA08,F 9.447880793

552 a,LA08,Ml,P,LA08,F 9.432127808

553 BHF,LA08,M1,P,L***,F 9.358572929

554 a,Ml,l,p,LA08,F 9.312301232

555 Ma,Ml,ML* * *,p,LA08,F 9.305536018

556 A,LA08,M1,P,1,F 9.275517312

557 A,L***,L***,P,LA08,F 9.266477273

558 LA02,ML***,BHF,p,l,F 9.240056979

559 a,Ml,BHF,P,ML***,F 9.195542246

560 BHF,l,BHF,p,LA08,F 9.169735085

561 MA,1,1,P,1,F 9.156141386

562 BHF,M1,L* * *,P,ML* * *,F 9.128480075

563 BHF,l,BHF,p,ML***,F 9.06582977

564 A,LA08,BHF,P,L***,F 9.060761253

565 a,ML***,Ml,p,LA08,F 9.048478377

566 LA02,ML* * * ,L* * *,p,Ml,F 9.047716444

567 Ma,L***,ML***,P,l,F 9.021357089

568 LA02,ML***,l,p,L***,F 8.993329364

569 A,LA08,LA08,p,LA08,F 8.989392592

570 BHF,L***,M1,P,1,F 8.988047245

571 MA,Ml,Ml,p,Ml,F 8.974656881

572 BHF,ML***,l,p,Ml,F 8.957058001

573 MA,l,ML***,p,L***,F 8.949936716

574 A,ML***,LA08,p,LA08,F 8.949298386

575 A,L***,L***,P,M1,F 8.924944906

576 MA,1,1,P,M1,F 8.923494816

577 MA,l,BHF,p,l,F 8.850533896

578 a,LA08,Ml,P,l,F 8.84662479

579 MA,1,L***,P,LA08,F 8.843453166

580 a,Ml,L***,p,LA08,F 8.843156174

581 BHF,M1,L* * *,P,L** *,F 8.837774041

582 LA02,M1,BHF,P,M1,F 8.801957256

583 LA02,l,LA08,p,L***,F 8.799123611 584 a,L***,Ml,P,ML***,F 8.783351487

585 BHF,LA08,L***,p,l,F 8.764049129

586 Ma,Ml,LA08,P,LA08,F 8.757968504

587 BHF,L***,L***,P,M1,F 8.708349082

588 BHF,l,LA08,p,Ml,F 8.698036413

589 BHF,l,L***,p,LA08,F 8.666959869

590 A,1,ML***,P,1,F 8.649168455

591 BHF,l,L***,p,LA08,F 8.624324092

592 A,LA08,L***,P,LA08,F 8.615162882

593 LA02,L A08 ,Ml,p,LA08 ,F 8.589641782

594 a,Ml,BHF,p,ML***,F 8.573690092

595 LA02,L***,L***,p,LA08,F 8.567734244

596 Ma,Ml,L***,p,LA08,F 8.510300222

597 BHF,l,L***,p,l,F 8.478559661

598 MA,LA08,Ml,p,l,F 8.476980949

599 LA02,Ml,LA08,p,ML* * *,F 8.453291457

600 A,l,Ml,p,ML***,F 8.423428825

601 BHF,M1,L***,P,M1,F 8.416794288

602 A,LA08,M1,P,LA08,F 8.379323649

603 a,LA08,l,p,ML***,F 8.37012376

604 Ma,l,l,P,l,F 8.346444716

605 Ma,Ml,Ml,p,Ml,F 8.332435709

606 Ma,l,BHF,P,ML***,F 8.30570999

607 Ma,l,L***,P,l,F 8.269826169

608 MA,ML***,L***,p,l,F 8.261007071

609 A,LA08,l,p,L***,F 8.2447995

610 a,L***,Ml,P,LA08,F 8.228769492

611 LA02,LA08,BHF,P,M1,F 8.216852927

612 a,ML***,l,p,LA08,F 8.203081879

613 LA02,LA08,Ml,p,Ml,F 8.191493245

614 MA,l,LA08,p,Ml,F 8.145248107

615 LA02,M1,BHF,P,M1,F 8.127230269

616 LA02,M1,L***,P,LA08,F 8.118609252

617 a,Ml,BHF,p,l,F 8.102601635

618 LA02,LA08,BHF,P,1,F 8.091902464

619 LA02,Ml,Ml,p,Ml,F 8.087341698

620 BHF,1,BHF,P,ML***,F 8.087125042

621 MA,LA08,L***,p,l,F 8.085861541

622 Ma,LA08,L***,P,l,F 8.054472566

623 a,LA08,L***,P,LA08,F 8.048127709

624 A,L***,Ml,p,Ml,F 8.046713312

625 LA02,ML* * * ,LA08 ,p,LA08 ,F 8.046674225

626 A,1,LA08,P,LA08,F 8.044443501

627 LA02,LA08,ML* * *,P,1,F 8.019399396 628 BHF,Ml,BHF,p,Ml,F 8.010904406

629 LA02,ML***,L***,p,l,F 8.004570537

630 Ma,L***,Ml,p,l,F 7.993062212

631 LA02,Ml,LA08,p,ML* * *,F 7.97665354

632 MA,Ml,Ml,p,Ml,F 7.937880559

633 a,ML***,l,p,Ml,F 7.893355922

634 A,ML***,L***,P,1,F 7.867367418

635 Ma,l,l,p,l,F 7.864537078

636 BHF,M1,M1,P,M1,F 7.851231014

637 LA02,LA08,LA08,p,l,F 7.837222558

638 a,ML***,l,P,Ml,F 7.813251831

639 a,Ml,BHF,P,l,F 7.793065895

640 a,LA08,LA08,P,LA08,F 7.758108471

641 LA02,1,LA08,P,LA08,F 7.748292417

642 LA02,1,1,P,LA08,F 7.731597276

643 LA02,Ml,Ml,p,LA08,F 7.730253597

644 LA02,Ml,LA08,p,LA08,F 7.688530783

645 MA,1,LA08,P,LA08,F 7.674105266

646 A,l,LA08,p,Ml,F 7.628702763

647 A,L***,M1,P,M1,F 7.623092282

648 Ma,ML***,BHF,p,LA08,F 7.615059868

649 MA,ML***,BHF,p,LA08,F 7.607566237

650 MA,L***,ML* * *,p,LA08,F 7.599284711

651 a,Ml,Ml,P,Ml,F 7.59776048

652 Ma,Ml,Ml,p,Ml,F 7.594492079

653 a,L***,Ml,P,l,F 7.575968604

654 A,Ml,LA08,p,Ml,F 7.56853665

655 Ma,L***,l,P,LA08,F 7.553279146

656 Ma,l,l,P,L***,F 7.54894806

657 Ma,l,l,p,LA08,F 7.465613977

658 MA,Ml,LA08,p,LA08,F 7.464612233

659 BHF,Ml,l,p,Ml,F 7.453519149

660 LA02,LA08,1,P,LA08,F 7.43726545

661 LA02,l,BHF,p,L***,F 7.429402282

662 LA02,LA08,LA08,p,l,F 7.419630776

663 LA02,l,Ml,p,Ml,F 7.402734165

664 LA02,M1,ML* * *,p,ML* * *,F 7.391575169

665 A,LA08,ML***,P,M1,F 7.34042489

666 a,Ml,ML***,p,L***,F 7.323662362

667 a,LA08,LA08,p,l,F 7.302210643

668 BHF,ML***,LA08,P,1,F 7.293312811

669 BHF,L***,ML***,p,LA08,F 7.267970912

670 BHF,1,BHF,P,1,F 7.266800993

671 MA,L***,LA08,p,LA08,F 7.258863301 672 A,l,LA08,p,L***,F 7.225489084

673 BHF,1,1,P,LA08,F 7.212470041

674 a,L***,LA08,P,LA08,F 7.188958972

675 LA02,LA08,LA08,P,LA08,F 7.175169234

676 LA02,LA08,LA08,P,L***,F 7.160087694

677 LA02,L***,L***,p,LA08,F 7.115171485

678 a,L***,l,P,Ml,F 7.113170196

679 BHF,LA08,1,P,1,F 7.041035412

680 A,L***,1,P,M1,F 7.040603365

681 a,Ml,l,P,l,F 7.03870328

682 LA02,ML***,LA08,P,LA08,F 7.035647254

683 Ma,ML***,l,P,l,F 7.017011869

684 a,Ml,LA08,p,LA08,F 7.011283929

685 A,L***,l,p,Ml,F 6.975808294

686 Ma,LA08,L***,P,l,F 6.959702972

687 LA02,ML***,LA08,P,LA08,F 6.943695894

688 BHF,L***,BHF,p,Ml,F 6.935705496

689 a,ML***,l,P,L***,F 6.917928868

690 Ma,L***,Ml,p,L***,F 6.916143735

691 LA02,l,BHF,p,Ml,F 6.903212049

692 Ma,l,BHF,p,LA08,F 6.882744451

693 A,L***,LA08,P,1,F 6.875531808

694 Ma,L***,LA08,P,LA08,F 6.824900307

695 a,L***,l,P,ML***,F 6.822741577

696 A,LA08,1,P,LA08,F 6.81157788

697 BHF,L***,M1,P,ML***,F 6.809746689

698 LA02,ML***,BHF,P,L***,F 6.791270429

699 BHF,L***,ML***,P,1,F 6.755272298

700 LA02,Ml,L***,p,ML***,F 6.749230183

701 LA02,Ml,ML***,p,Ml,F 6.747900026

702 BHF,L***,LA08,P,1,F 6.720235555

703 MA,l,BHF,p,LA08,F 6.685521839

704 A,L***,LA08,p,l,F 6.682576235

705 LA02,L***,BHF,P,L***,F 6.681723993

706 MA,M1,1,P,LA08,F 6.654625468

707 LA02,l,Ml,p,Ml,F 6.603141301

708 a,l,BHF,p,l,F 6.601010658

709 BHF,L***,L***,P,LA08,F 6.596594725

710 LA02,LA08,BHF,P,L* * *,F 6.590767157

711 a,LA08,l,P,LA08,F 6.542426979

712 a,Ml,l,P,L***,F 6.532408763

713 BHF,1,BHF,P,LA08,F 6.499409236

714 LA02,L***,1,P,1,F 6.436337086

715 BHF,LA08,BHF,P,L***,F 6.320166945 716 A,LA08,ML***,P,ML***,F 6.291937124

717 a,l,LA08,P,LA08,F 6.253940796

718 LA02,l,L***,p,L***,F 6.250077616

719 BHF,M1,BHF,P,1,F 6.245065973

720 a,l,BHF,p,Ml,F 6.230284798

721 BHF,LA08,1,P,M1,F 6.204256998

722 A,ML***,LA08,p,Ml,F 6.186737279

723 MA,L***,L***,p,Ml,F 6.180292332

724 A,M1,BHF,P,L***,F 6.173418821

725 BHF,L***,ML***,P,LA08,F 6.166490266

726 BHF,LA08,Ml,p,Ml,F 6.152430163

727 LA02,L***,BHF,p,l,F 6.127555176

728 a,LA08,ML***,p,ML***,F 6.114988928

729 A,LA08,ML***,P,1,F 6.102511913

730 A,Ml,Ml,p,Ml,F 6.094306779

731 LA02,LA08,L***,p,LA08,F 6.080538292

732 BHF,l,ML***,p,LA08,F 6.073384376

733 Ma,L***,L***,p,Ml,F 6.062607317

734 LA02,M1,M1,P,M1,F 6.043175019

735 BHF,M1,1,P,ML***,F 6.039999151

736 Ma,Ml,L***,p,l,F 6.038344336

737 BHF,LA08,ML***,P,L***,F 6.029179956

738 BHF,ML***,Ml,p,Ml,F 5.962395369

739 a,l,LA08,p,ML***,F 5.952173707

740 a,Ml,LA08,P,L***,F 5.952015047

741 LA02,LA08,l,p,L***,F 5.849625283

742 BHF,l,L***,p,ML***,F 5.8405699

743 LA02,l,L***,p,L***,F 5.834238188

744 A,l,l,p,LA08,F 5.801327507

745 LA02,L***,Ml,p,LA08,F 5.796177059

746 MA,ML***,BHF,p,LA08,F 5.796105762

747 a,L***,L***,P,LA08,F 5.774621052

748 BHF,L***,1,P,LA08,F 5.762289714

749 LA02,M1,1,P,LA08,F 5.732089574

750 MA,Ml,L***,p,l,F 5.729766862

751 a,LA08,l,p,Ml,F 5.722356207

752 LA02,L***,l,p,l,F 5.681169623

753 Ma,Ml,BHF,P,l,F 5.679997044

754 MA,LA08,ML***,P,M1,F 5.642892187

755 MA,LA08,l,p,LA08,F 5.628456201

756 Ma,Ml,BHF,p,l,F 5.6180916

757 BHF,M1,L***,P,LA08,F 5.614251779

758 LA02,Ml,BHF,p,Ml,F 5.604317419

759 BHF,l,l,p,L***,F 5.598423026 760 a,LA08,BHF,p,ML***,F 5.595643211

761 a,Ml,Ml,P,Ml,F 5.58553753

762 BHF,Ml,L***,p,l,F 5.582865938

763 a,LA08,l,P,LA08,F 5.564052656

764 Ma,L***,l,p,LA08,F 5.54833614

765 LA02,ML***,M1,P,LA08,F 5.539608771

766 BHF,LA08,BHF,p,l,F 5.523929465

767 A,L***,M1,P,1,F 5.498324786

768 A,M1,1,P,1,F 5.467952168

769 Ma,ML***,LA08,p,Ml,F 5.462668405

770 A,ML***,LA08,P,1,F 5.450254902

771 a,LA08,LA08,p,l,F 5.3981743

772 BHF,L***,LA08,p,Ml,F 5.384658442

773 Ma,l,BHF,P,Ml,F 5.37358175

774 A,1,BHF,P,1,F 5.333276911

775 a,ML***,BHF,P,LA08,F 5.322246179

776 A,Ml,LA08,p,Ml,F 5.303308773

777 BHF,M1,LA08,P,M1,F 5.299551298

778 LA02,1,M1,P,M1,F 5.291625049

779 Ma,LA08,ML***,P,l,F 5.279177817

780 LA02,Ml,l,p,l,F 5.276656133

781 BHF,ML***,LA08,p,LA08,F 5.268923867

782 MA,l,LA08,p,LA08,F 5.259222912

783 Ma,ML***,BHF,p,l,F 5.255010107

784 Ma,LA08,BHF,P,L***,F 5.251781145

785 LA02,l,l,p,LA08,F 5.237026512

786 a,L***,l,p,Ml,F 5.197078286

787 Ma,l,L***,P,LA08,F 5.18849604

788 LA02,ML* * * ,1,P,L* * * ,F 5.170969683

789 LA02,l,BHF,p,L***,F 5.163029145

790 BHF,LA08,L***,p,Ml,F 5.157084708

791 LA02,Ml,LA08,p,ML* * *,F 5.140152542

792 MA,M1,M1,P,M1,F 5.125129024

793 BHF,LA08,LA08,p,l,F 5.110278738

794 A,1,1,P,M1,F 5.110183983

795 a,L***,l,p,LA08,F 5.05005887

796 a,Ml,BHF,P,LA08,F 5.026004109

797 MA,L***,1,P,L***,F 5.022181461

798 BHF,M1,1,P,M1,F 5.014468783

799 a,LA08,Ml,p,l,F 5.01218403

800 A,1,BHF,P,ML***,F 5.008957941

801 A,LA08,Ml,p,L***,F 4.999599179

802 MA,Ml,LA08,p,L***,F 4.987967246

803 MA,M1,BHF,P,M1,F 4.98242252 804 A,LA08,1,P,1,F 4.971700529

805 A 1 L*** p L*** p 4.955513875

806 BHF,M1,ML* * *,P,ML* * *,F 4.949040241

807 MA,M1,M1,P,M1,F 4.925309949

808 MA,ML***,BHF,p,l,F 4.92064853

809 A,1,BHF,P,LA08,F 4.920431357

810 a,l,BHF,P,ML***,F 4.918630557

811 a,LA08,Ml,P,LA08,F 4.887620717

812 BHF,Ml,l,p,ML***,F 4.853776703

813 a,L***,Ml,p,l,F 4.818220363

814 a,l,BHF,P,LA08,F 4.798780921

815 a,LA08,L***,p,L***,F 4.730771203

816 LA02,1,1,P,M1,F 4.679523254

817 A,l,BHF,p,Ml,F 4.661421409

818 BHF,L***,LA08,p,LA08,F 4.650276938

819 LA02,l,LA08,p,LA08,F 4.645548262

820 MA,L***,L***,p,LA08,F 4.645204105

821 BHF,L***,Ml,p,ML***,F 4.560491954

822 A,1,1,P,L***,F 4.558809103

823 MA,L***,BHF,p,LA08,F 4.558093826

824 BHF,M1,L* * *,p,ML* * *,F 4.540809527

825 BHF,L***,L***,P,1,F 4.496476521

826 a,Ml,Ml,P,Ml,F 4.489806331

827 MA,1,M1,P,1,F 4.481489595

828 Ma,L***,l,p,Ml,F 4.439123536

829 LA02,LA08,LA08,p,LA08,F 4.413765128

830 LA02,L***,L***,P,1,F 4.397697324

831 LA02,l,l,p,L***,F 4.379675726

832 A,L***,1,P,1,F 4.343619858

833 MA,1,LA08,P,L***,F 4.292368636

834 a,l,L***,P,LA08,F 4.292139985

835 Ma,l,LA08,P,LA08,F 4.285097752

836 LA02,L* **,LA08,p,L* * *,F 4.230986934

837 a,LA08,l,P,l,F 4.207597614

838 Ma,l,ML***,p,L***,F 4.20015786

839 BHF,M1,M1,P,1,F 4.186196982

840 a,ML***,BHF,P,l,F 4.18179341

841 BHF,Ml,l,p,ML***,F 4.157185489

842 LA02,LA08,LA08,P,L***,F 4.140926176

843 Ma,l,LA08,p,LA08,F 4.138746826

844 MA,LA08,LA08,P,LA08,F 4.06024523

845 a,l,LA08,P,Ml,F 4.047409136

846 BHF,L***,M1,P,LA08,F 4.027404683

847 A,l,l,p,ML***,F 3.998229076 848 MA,L***,L***,P,M1,F 3.99591015

849 Ma,LA08,BHF,p,ML***,F 3.986868127

850 LA02,Ml,BHF,p,Ml,F 3.943742224

851 A,M1,BHF,P,1,F 3.940021

852 A,ML***,l,p,L***,F 3.9357447

853 A,ML***,l,p,Ml,F 3.933263636

854 A,1,ML***,P,1,F 3.912148737

855 a,Ml,BHF,p,Ml,F 3.822583984

856 MA,1,BHF,P,ML***,F 3.816794499

857 MA,M1,M1,P,M1,F 3.799446452

858 BHF,M1,M1,P,M1,F 3.792816741

859 MA,Ml,l,p,L***,F 3.78573774

860 a,LA08,LA08,p,LA08,F 3.779480912

861 BHF,L***,BHF,P,ML***,F 3.77844294

862 Ma,l,l,P,Ml,F 3.75684075

863 BHF,ML***,LA08,p,Ml,F 3.702677784

864 a,L***,L***,P,Ml,F 3.701467648

865 a,l,LA08,p,Ml,F 3.68847873

866 a,L***,l,p,l,F 3.680001237

867 Ma,L***,LA08,p,LA08,F 3.674158941

868 LA02,1,BHF,P,LA08,F 3.672058035

869 LA02,l,l,p,Ml,F 3.670730924

870 3.661227149

871 MA,L***,1,P,1,F 3.648335683

872 BHF,ML***,LA08,p,l,F 3.646265202

873 A,ML***,1,P,1,F 3.639896025

874 BHF,M1,M1,P,1,F 3.614011685

875 MA,ML***,L***,P,1,F 3.613970739

876 a,LA08,ML* * *,p,LA08,F 3.565440407

877 LA02,ML***,L* * *,p,LA08,F 3.513531711

878 a,Ml,LA08,P,l,F 3.509375384

879 MA,Ml,BHF,p,l,F 3.47207946

880 LA02,LA08,L** *,p,ML* * *,F 3.468532214

881 A,Ml,l,p,L***,F 3.467292771

882 Ma,Ml,LA08,p,LA08,F 3.449889179

883 LA02,ML***,LA08,p,L***,F 3.422626161

884 a,Ml,l,p,l,F 3.413045384

885 MA,M1,L***,P,1,F 3.411058229

886 LA02,M1,1,P,LA08,F 3.398787948

887 Ma,l,BHF,P,L***,F 3.363638424

888 A,L***,1,P,1,F 3.342324735

889 BHF,1,LA08,P,LA08,F 3.336977214

890 Ma,l,BHF,p,Ml,F 3.328291543

891 Ma,l,BHF,P,LA08,F 3.29864556 892 A,1,BHF,P,L***,F 3.283361952

893 BHF,M1,1,P,LA08,F 3.282990164

894 a,L***,Ml,p,L***,F 3.265382315

895 MA,Ml,l,p,l,F 3.24089528

896 BHF,M1,LA08,P,ML* * *,F 3.233604517

897 a,Ml,BHF,P,Ml,F 3.219899095

898 a,Ml,BHF,p,LA08,F 3.209271364

899 BHF,ML***,LA08,p,Ml,F 3.203077023

900 a,L***,l,P,LA08,F 3.192997038

901 a,Ml,LA08,p,L***,F 3.188836831

902 LA02,L* **,ML* * *,p,LA08,F 3.186920091

903 MA,LA08,BHF,p,l,F 3.170561209

904 BHF,LA08,LA08,P,1,F 3.16955984

905 BHF,M1,L***,P,M1,F 3.163553756

906 Ma,LA08,BHF,p,l,F 3.158294592

907 Ma,Ml,Ml,p,Ml,F 3.150790127

908 BHF,LA08,M1,P,LA08,F 3.096760797

909 LA02,Ml,Ml,p,l,F 3.09466279

910 MA,ML***,l,p,LA08,F 3.090144419

911 A,LA08,LA08,p,L***,F 3.064018713

912 a,L***,l,P,l,F 3.054271484

913 BHF,LA08,BHF,P,1,F 3.051380451

914 a,Ml,Ml,p,Ml,F 3.049366565

915 Ma,LA08,l,p,L***,F 3.010185207

916 BHF,M1,ML***,P,M1,F 2.995666887

917 A,1,1,P,1,F 2.99007427

918 a,ML***,l,P,l,F 2.946257625

919 MA,l,Ml,p,L***,F 2.944306232

920 Ma,LA08,LA08,P,LA08,F 2.918329696

921 a,l,Ml,p,l,F 2.887948226

922 Ma,l,l,P,LA08,F 2.86571319

923 LA02,Ml,BHF,p,Ml,F 2.864702906

924 Ma,L***,ML***,p,l,F 2.86160219

925 MA,M1,M1,P,M1,F 2.831646367

926 A,Ml,l,p,l,F 2.827508693

927 Ma,LA08,l,p,L***,F 2.817673975

928 Ma,Ml,Ml,p,Ml,F 2.779684151

929 a,l,LA08,P,l,F 2.750737412

930 LA02,ML***,BHF,p,Ml,F 2.743938266

931 a,L***,LA08,P,l,F 2.722944496

932 MA,ML***,BHF,P,1,F 2.710500596

933 MA,L***,1,P,LA08,F 2.709421124

934 a,Ml,Ml,p,l,F 2.704207233

935 LA02,ML***,BHF,p,LA08,F 2.631383083 936 LA02,L***,L***,p,l,F 2.616954756

937 BHF,M1,LA08,P,ML* * *,F 2.609283785

938 Ma,Ml,BHF,P,Ml,F 2.5838208

939 a,l,L***,P,ML***,F 2.573450027

940 BHF,ML***,LA08,P,LA08,F 2.558926316

941 A,l,l,p,l,F 2.552894905

942 MA,l,LA08,p,L***,F 2.546867999

943 a,l,Ml,P,Ml,F 2.53015786

944 MA,M1,L***,P,L***,F 2.507583547

945 Ma,l,l,p,ML***,F 2.483452527

946 Ma,l,BHF,p,Ml,F 2.482115084

947 Ma,LA08,BHF,p,Ml,F 2.45866909

948 MA,Ml,Ml,p,l,F 2.430356628

949 A,l,l,p,Ml,F 2.392962435

950 a,Ml,LA08,p,Ml,F 2.366270393

951 MA,1,ML***,P,L***,F 2.343324006

952 a,L***,BHF,p,l,F 2.340204055

953 BHF,ML***,M1,P,LA08,F 2.334566318

954 a,l,l,P,LA08,F 2.322052743

955 MA,1,1,P,M1,F 2.321953035

956 BHF,ML***,LA08,P,LA08,F 2.317827141

957 MA,LA08,BHF,P,1,F 2.315571818

958 BHF,LA08,LA08,p,Ml,F 2.28082983

959 A,1,BHF,P,M1,F 2.267306184

960 a,L***,Ml,p,Ml,F 2.262653009

961 MA,1,BHF,P,L***,F 2.236342237

962 BHF,L***,LA08,P,LA08,F 2.224107332

963 MA,L***,LA08,P,1,F 2.220888577

964 BHF,Ml,LA08,p,l,F 2.200773477

965 a,l,Ml,p,ML***,F 2.150885314

966 Ma,Ml,BHF,p,LA08,F 2.130913971

967 BHF,ML***,LA08,p,ML***,F 2.113078776

968 BHF,l,LA08,p,LA08,F 2.097299106

969 MA,1,1,P,L***,F 2.097240979

970 MA,M1,BHF,P,M1,F 2.084457722

971 MA,M1,LA08,P,1,F 2.019124535

972 a,LA08,l,p,l,F 1.986395902

973 MA,1,BHF,P,M1,F 1.976703241

974 MA,1,BHF,P,M1,F 1.976703241

975 a,ML***,l,p,ML***,F 1.949056916

976 Ma,LA08,LA08,p,LA08,F 1.931680012

977 a,l,LA08,P,L***,F 1.917554286

978 a,L***,L***,p ,1,F 1.896665982

979 MA,LA08,LA08,p,LA08,F 1.891875636 980 BHF,ML***,LA08,P,M1,F 1.889646603

981 BHF,ML***,M1,P,M1,F 1.884015652

982 MA,l,BHF,p,L***,F 1.878245365

983 MA,l,L***,p,L***,F 1.808753284

984 BHF,LA08,L* * *,P,LA08,F 1.800796374

985 BHF,1,LA08,P,LA08,F 1.800065615

986 BHF,ML***,ML***,P,LA08,F 1.771227842

987 Ma,L***,BHF,P,L***,F 1.764502925

988 BHF,LA08,BHF,P,M1,F 1.749745372

989 MA,M1,BHF,P,1,F 1.702128466

990 Ma,l,l,p,Ml,F 1.644239055

991 a,L***,l,p,l,F 1.607246122

992 BHF,Ml,BHF,p,Ml,F 1.571943589

993 BHF,ML***,LA08,p,LA08,F 1.569937417

994 MA,l,l,p,LA08,F 1.505486657

995 MA,LA08,L***,P,1,F 1.505202515

996 Ma,LA08,l,p,l,F 1.497100343

997 BHF,LA08,LA08,p,L***,F 1.489150081

998 Ma,L***,l,P,l,F 1.480181817

999 MA,Ml,Ml,p,l,F 1.462990076

1000 BHF,Ml,l,p,LA08,F 1.447153033

1001 Ma,Ml,Ml,P,l,F 1.390305635

1002 a,l,BHF,P,Ml,F 1.33946399

1003 Ma,L***,l,P,LA08,F 1.326574827

1004 MA,L***,l,p,LA08,F 1.324580747

1005 BHF,ML***,ML***,P,M1,F 1.324471746

1006 MA,LA08,L***,p,LA08,F 1.314797814

1007 BHF,ML***,LA08,p,Ml,F 1.210283521

1008 MA,L***,BHF,p,l,F 1.198411999

1009 a,l,l,p,l,F 1.167434745

1010 MA,L***,L***,p,l,F 1.159476244

1011 Ma,Ml,Ml,p,l,F 1.15303301

1012 MA,l,l,p,L***,F 1.140630815

1013 LA02,M1,ML* * *,p,L** *,F 1.136297368

1014 BHF,Ml,L***,p,Ml,F 1.127409942

1015 Ma,L***,l,p,l,F 1.116819581

1016 a,l,l,P,Ml,F 1.110903769

1017 BHF,LA08,LA08,p,Ml,F 1.103406979

1018 Ma,Ml,Ml,p,l,F 1.040434901

1019 MA,1,L***,P,L***,F 1.029054628

1020 Ma,L***,L***,P,l,F 1.025434776

1021 a,l,l,p,LA08,F 1.018947064

1022 Ma,l,l,p,LA08,F 0.970181534

1023 a,l,LA08,p,L***,F 0.963388403

MSMS Processing Centroided MS2 spectra first had their parent ion mass corrected to high resolution by locating the closest high resolution mass in the MS 1 spectrum, then filtered down to those spectra matching masses of the sublibrary of interest. MS2 spectra were then grouped per their source-peak, before using the most intense as a base spectrum for intensity combination.

Combination occurred by a one-to-one m/z correspondence rule with the closest m/z being matched between spectra. In a separate process, all MS2 spectra (pre-filtration) had their peak intensities collected into a single dataset, which was filtered to the lowest 90% and used to generate a kernel density estimate of the noise distribution. From that noise distribution, a noise threshold was decided by setting it to the p-value of 0.05 of a noise peak having intensity equal to or greater than the threshold. Finally, intensity-combined MS2 spectra were filtered by peak intensity at that threshold.

Sequencing

Each MS2 spectrum was first matched at high resolution (0.015 m/z) to all possible parent compounds from the library design. All possible fragment masses were belonging to those possible parent compounds were generated, then matched against the MS2 spectrum peaks. Based on those matches, a best candidate was identified. Number of matches, identity of matches, and peak intensity were all included in the scoring of each candidate molecule.

Data Correlation

Permeability data and sequencing data were correlated by mass and retention time matches within large precision gaps to account for inter-run variability (time precision = 3 seconds, mass precision = 0.03). The data were then pruned of those peaks for which no Pe value could be calculated and with unacceptably low sequencing quality (generally due to poor MS2 data quality).

Abbreviations

ACN, acetonitrile; COMU, (l-Cyano-2-ethoxy-2- oxoethylidenaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate; DBU, 1,8- Diazabicyclo[5.4.0]undec-7-ene; DCM, dichloromethane; DMF, N,N-dimethylformamide; DIPEA, diisopropylethylamine, DMSO, dimethylsulf oxide; Fmoc, 9-fluorenylmethoxycarbonyl; HATU, l-[Bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyri dinium 3-oxide hexafluorophosphate; LCMS, liquid chromatography mass spectrometry; MeOH, methanol; N2, nitrogen; PTFE, Polytetrafluoroethylene; RP, reverse phase; SPPS, solid phase peptide synthesis; TFA, trifluoroacetic acid.

PAMPA Permeability of Resynthesized Compounds

A set of hexapeptomers were resynthesized and the parallel artificial membrane permeability assay was performed to determine the permeability values. Each peptomer sequence with determined permeability (Pe) value is shown in Table 3.

Table 3

Aspects, including embodiments, of the subject matter described herein may be beneficial alone or in combination, with one or more other aspects or embodiments. Without limiting the description, certain non-limiting aspects of the disclosure numbered 1-68 are provided below. As will be apparent to those of skill in the art upon reading this disclosure, each of the individually numbered aspects may be used or combined with any of the preceding of following individually numbered aspects. This is intended to provide support for all such combinations of aspects and is not limited to combinations of aspects explicitly provided below:

1. A compound of Formula I:

Cyclo [Z-Y-X-Pro-Y-Phe] Formula I

each Ri is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl, or optionally, Ri together with the atoms to which it is bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring;

each R2 is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl, or optionally, Ri together with the atoms to which it is bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring;

each R3 is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl, or optionally, R _! together with the atoms to which it is bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring;

A is selected from -NR _a -, -O- or -S-;

B is selected from -NRt,-, -O- or -S-;

C is selected from -NR _C -, -O- or -S-;

each R _a , R _b , R _c is independently selected from hydrogen, alkyl, substituted alkyl, aryl and substituted aryl, or Ri and R _a together with the atoms to which they are bonded form a

cycloheteroalkyl or substituted cycloheteroalkyl ring;

R2 and R _b together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring;

R ₃ and R _c together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring;

n is an integer from one to 5 and a is an integer from one to 5;

p is an integer from one to 5 and b is an integer from one to 5; and

r is an integer from one to 5 and c is an integer from one to 5 ;

or a pharmaceutical acceptable salt, solvate or hydrate thereof.

2. The compound according to 1, wherein each Ri is independently selected from a side chain of an amino acid selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glycine, glutamine, glutamic acid, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine.

3. The compound according to 2, wherein each R _! is independently selected from a side chain of glycine, leucine or phenylalanine.

4. The compound according to any one of 1-3, wherein each R2 is independently selected from a side chain of an amino acid selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glycine, glutamine, glutamic acid, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine.

n:

n:

7. The compound according to 6, wherein each R2 is independently selected from a side chain of leucine or glycine.

8. The compound according to any one of 1-7, wherein each R ₃ is independently selected from a side chain of an amino acid selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glycine, glutamine, glutamic acid, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine.

9. The compound according to 8, wherein each R ₃ is independently selected from a side chain of glycine, alanine or phenylalanine.

10. The compound according to any one of 1-9, wherein n is 2 and each Ri is selected from a side chain of glycine or phenylalanine.

11. The compound according to any one of 1-10, wherein r is 2 and each R ₃ is selected from a side chain of glycine or phenylalanine.

12. The compound according to any one of 1-11, wherein p is 1 and R2 is glycine or leucine.

13. The compound according to any one of 1-12, wherein A is NR _a .

14. The compound according to 13, wherein R _a is selected from hydrogen, alkyl or aryl.

15. The compound according to 14, wherein the alkyl is methyl or propyl.

16. The compound according to 14, wherein the aryl is benzyl.

17. The compound according to any one of 1-16, wherein B is NR _t ,.

18. The compound according to 17, wherein R _b is selected from hydrogen, alkyl or aryl.

19. The compound according to 18, wherein the alkyl is methyl.

20. The compound according to 18, wherein the aryl is benzyl.

21. The compound according to any one of 1-20, wherein C is NR _C .

22. The compound according to 21, wherein R _c is selected from hydrogen, alkyl or aryl.

23. The compound according to 22, wherein the alkyl is methyl.

24. The compound according to 22, wherein the aryl is benzyl.

25. The compound according to any one of 1-24, wherein X is a residue of a D- amino acid or L-amino acid selected from alanine, arginine, asparagine, aspartic acid, cysteine, glycine, glutamine, glutamic acid, histidine, isoleucine, leucine, lysine, methionine,

phenylalanine, β-homophenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine or an N-alkyl derivative thereof.

26. The compound according to 25, wherein X is a D-amino acid selected from alanine, arginine, asparagine, aspartic acid, cysteine, glycine, glutamine, glutamic acid, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, β-homophenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine or an N-alkyl derivative thereof.

27. The compound according to 26, wherein X is D-leucine or an N-alkyl derivative thereof.

28 The compound according to 27, wherein X is D-leucine.

29. The compound according to 27, wherein X is N-methyl D-leucine.

30. The compound according to 25, wherein X is an L-amino acid selected from alanine, arginine, asparagine, aspartic acid, cysteine, glycine, glutamine, glutamic acid, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, β-homophenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine or an N-alkyl derivative thereof.

31. The compound according to 30, wherein X is L-leucine or an N-alkyl derivative thereof.

32. The compound according to 27, wherein X is L-leucine.

33. The compound according to 27, wherein X is N-methyl L-leucine.

34. The compound according to 30, wherein X is L- -homophenylalanine or an alkyl derivative thereof.

35. The compound according to 30, wherein X is L- -homophenylalanine.

36. The compound according to 25, wherein X is glycine or an N-alkyl derivative thereof.

37. The compound according to 36, wherein X is N-benzyl glycine.

38. The compound according to any one of 1-37, wherein Y is a residue of a D- amino acid or L-amino acid selected from alanine, arginine, asparagine, aspartic acid, cysteine, glycine, glutamine, glutamic acid, histidine, isoleucine, leucine, lysine, methionine,

phenylalanine, β-homophenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine or an N-alkyl derivative thereof.

39. The compound according to 38, wherein Y is a D-amino acid selected from alanine, arginine, asparagine, aspartic acid, cysteine, glycine, glutamine, glutamic acid, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, β-homophenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine or an N-alkyl derivative thereof.

40. The compound according to 39, wherein Y is D-leucine or an N-alkyl derivative thereof.

41 The compound according to 40, wherein Y is D-leucine.

42. The compound according to 40, wherein Y is N-methyl D-leucine. 43. The compound according to 38, wherein Y is an L-amino acid selected from alanine, arginine, asparagine, aspartic acid, cysteine, glycine, glutamine, glutamic acid, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, β-homophenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine or an N-alkyl derivative thereof.

44. The compound according to 43, wherein Y is L-leucine or an N-alkyl derivative thereof.

45. The compound according to 44, wherein Y is L-leucine.

46. The compound according to 44, wherein Y is N-methyl L-leucine.

47. The compound according to 38, wherein Y is glycine or an N-alkyl derivative thereof.

48. The compound according to 47, wherein Y is N-benzyl glycine.

49. The compound according to any one of 1-48, wherein Z is a residue of a D-amino acid or L-amino acid selected from alanine, arginine, asparagine, aspartic acid, cysteine, glycine, glutamine, glutamic acid, histidine, isoleucine, leucine, lysine, methionine,

phenylalanine, β-homophenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine or an N-alkyl derivative thereof.

50. The compound according to 49, wherein Z is a D-amino acid selected from alanine, arginine, asparagine, aspartic acid, cysteine, glycine, glutamine, glutamic acid, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, β-homophenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine or an N-alkyl derivative thereof.

51. The compound according to 50, wherein Z is D-alanine or an N-alkyl derivative thereof.

52. The compound according to 51 , wherein Z is D-alanine.

53. The compound according to 51, wherein Z is N-methyl D-leucine.

54. The compound according to 49, wherein Z is an L-amino acid selected from alanine, arginine, asparagine, aspartic acid, cysteine, glycine, glutamine, glutamic acid, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, β-homophenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine or an N-alkyl derivative thereof.

55. The compound according to 54, wherein Z is L-alanine or an N-alkyl derivative thereof.

56. The compound according to 55, wherein Z is L-alanine.

57. The compound according to 55, wherein Z is N-methyl L-alanine. 58. The compound according to 49, wherein Z is L- -homophenylalanine or an alkyl derivative thereof.

59. The compound according to 30, wherein Z is L- -homophenylalanine.

60. The compound according to 49, wherein Z is glycine or an N-alkyl derivative thereof.

61. The compound according to 36, wherein Z is N-propyl glycine.

62. A compound of Formula 1 :

or a pharmaceutical acceptable salt, solvate or hydrate thereof.

63. A compound of Formula 2 :

Formula 2

or a pharmaceutical acceptable salt, solvate or hydrate thereof.

64. A composition comprising:

a compound or pharmaceutically acceptable salt, solvate or hydrate thereof according to any one of 1-63; and

a pharmaceutically acceptable vehicle. 65. The composition according to 64, wherein the composition comprises:

a compound according to any one of 1-63; and

a pharmaceutically acceptable vehicle.

66. A method comprising administering a compound or pharmaceutically acceptable salt, solvate or hydrate thereof according to any one of 1-63 to a subject.

67. A method comprising administering a composition according to any one of 64-65 to a subject.

68. A library comprising 50 or more cyclic peptides, each cyclic peptide

independently having a Formula I:

Cyclo [Z-Y-X-Pro-Y-Phe] Formula I

each Ri is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl, or optionally, together with the atoms to which it is bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring;

each P2 is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl, or optionally, Ri together with the atoms to which it is bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring; each R3 is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl, or optionally, Ri together with the atoms to which it is bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring;

A is selected from -NR _a -, -O- or -S-;

B is selected from -NRt,-, -O- or -S-;

C is selected from -NR _C -, -O- or -S-;

each R _a , R _b , R _c is independently selected from hydrogen, alkyl, substituted alkyl, aryl and substituted aryl, or

Ri and R _a together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring;

R2 and R _b together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring;

R ₃ and R _c together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring;

n is an integer from one to 5 and a is an integer from one to 5;

p is an integer from one to 5 and b is an integer from one to 5; and

r is an integer from one to 5 and c is an integer from one to 5 ;

or a pharmaceutical acceptable salt, solvate or hydrate thereof.

Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it is readily apparent to those of ordinary skill in the art in light of the teachings of this invention that certain changes and modifications may be made thereto without departing from the spirit or scope of the appended claims. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.

Accordingly, the preceding merely illustrates the principles of the invention. It will be appreciated that those skilled in the art will be able to devise various arrangements which, although not explicitly described or shown herein, embody the principles of the invention and are included within its spirit and scope. Furthermore, all examples and conditional language recited herein are principally intended to aid the reader in understanding the principles of the invention and the concepts contributed by the inventors to furthering the art, and are to be construed as being without limitation to such specifically recited examples and conditions. Moreover, all statements herein reciting principles, aspects, and embodiments of the invention as well as specific examples thereof, are intended to encompass both structural and functional equivalents thereof. Additionally, it is intended that such equivalents include both currently known equivalents and equivalents developed in the future, i.e., any elements developed that perform the same function, regardless of structure. The scope of the present invention, therefore, is not intended to be limited to the exemplary embodiments shown and described herein. Rather, the scope and spirit of present invention is embodied by the appended claims.