WO2016057656A1 - Agonistes ppar-delta destinés à être utilisés pour le traitement d'affections mitochondriales, vasculaires, musculaires et démyélynisantes - Google Patents

Agonistes ppar-delta destinés à être utilisés pour le traitement d'affections mitochondriales, vasculaires, musculaires et démyélynisantes Download PDF

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WO2016057656A1
WO2016057656A1 PCT/US2015/054473 US2015054473W WO2016057656A1 WO 2016057656 A1 WO2016057656 A1 WO 2016057656A1 US 2015054473 W US2015054473 W US 2015054473W WO 2016057656 A1 WO2016057656 A1 WO 2016057656A1
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disease
aliphatic
alkyl
ppar5
optionally substituted
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PCT/US2015/054473
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English (en)
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Michael Downes
Ronald Evans
Kazumi Shiosaki
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Mitobridge, Inc.
Salk Institute For Biological Studies
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Publication of WO2016057656A1 publication Critical patent/WO2016057656A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4192—1,2,3-Triazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • This application concerns methods of treating mitochondrial, vascular, muscular, and demyelinating diseases, and other related conditions, with PPAR delta (PPAR5) agonists.
  • Mitochondrial diseases can be very debilitating and can substantially reduce the quality of life of the patient. Accordingly, there is a great need in the art for novel methods of effectively and reliably mitochondrial diseases.
  • the present invention addresses these and other such needs.
  • PPAR5- related diseases e.g., mitochondrial diseases, muscular diseases, demyelinating diseases, and vascular diseases.
  • methods modulating the activity of PPAR5 for the treatment of diseases, developmental delays, and symptoms related to mitochondrial dysfunction see, e.g., Examples 1-7).
  • the disclosed compounds and compositions are useful in the treatment of mitochondrial diseases, such as Alpers's Disease, CPEO-Chronic progressive external ophthalmoplegia, Kearns-Sayra Syndrome (KSS), Leber Hereditary Optic Neuropathy (LHON), MELAS -Mitochondrial myopathy, encephalomyopathy, lactic acidosis, and stroke-like episodes, MERRF-Myoclonic epilepsy and ragged-red fiber disease, NARP-neurogenic muscle weakness, ataxia, and retinitis pigmentosa, and Pearson Syndrome.
  • mitochondrial diseases such as Alpers's Disease, CPEO-Chronic progressive external ophthalmoplegia, Kearns-Sayra Syndrome (KSS), Leber Hereditary Optic Neuropathy (LHON), MELAS -Mitochondrial myopathy, encephalomyopathy, lactic acidosis, and stroke-like episodes, MERRF-Myoclonic epilepsy and
  • a method of treating a PPAR5-related disease or condition in a subject comprising administering to the subject a therapeutically effective amount of a PPAR5 agonist, wherein the PPAR5-related disease or condition is a vascular disease, a muscular disease, or a demyelinating disease.
  • a method of treating a PPAR5-related disease or condition in a subject comprising administering to the subject a therapeutically effective amount of a PPAR5 agonist, wherein the PPAR5-related disease or condition is a muscle structure disorder, a neuronal activation disorder, a muscle fatigue disorder, a muscle mass disorder, a mitochondrial disease, a beta oxidation disease, a vascular disease, an ocular vascular disease, or a muscular eye disease.
  • provided herein is a method of increasing or maintaining muscle mass or muscle tone in a subject, comprising administering to the subject a therapeutically effective amount of a PPAR5 agonist.
  • PPAR5 agonists or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising one or more PPAR5 agonists, for the preparation of a medicament for the treatment of a PPAR5-related disease or condition
  • the PPAR5-related disease or condition is a vascular disease, a muscular disease, or a demyelinating disease.
  • the use of the PPAR5 agonists is intended for the treatment of a subject with PPAR5-related disease or condition selected from a muscle structure disorder, a neuronal activation disorder, a muscle fatigue disorder, a muscle mass disorder, a mitochondrial disease, a beta oxidation disease, a vascular disease, an ocular vascular disease, or a muscular eye disease.
  • PPAR5-related disease or condition selected from a muscle structure disorder, a neuronal activation disorder, a muscle fatigue disorder, a muscle mass disorder, a mitochondrial disease, a beta oxidation disease, a vascular disease, an ocular vascular disease, or a muscular eye disease.
  • the use of the PPAR5 agonists is intended for increasing or maintaining muscle mass or muscle tone in a subject.
  • one or more PPAR5 agonists, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising one or more PPAR5 agonists, for use in a method for treating a PPAR5-related disease or condition selected from a muscle structure disorder, a neuronal activation disorder, a muscle fatigue disorder, a muscle mass disorder, a mitochondrial disease, a beta oxidation disease, a vascular disease, an ocular vascular disease, or a muscular eye disease.
  • the PPAR5 agonists are for use in a method to increase or maintain muscle mass or muscle tone in a subject.
  • Figures 1A and IB are bar graphs showing recovery of damaged muscle fibers after injury.
  • Figures 1C-1F show VP16-PPAR5 transgenic animals exhibit accelerated muscle regeneration after acute injury. All error bars are SEM.
  • Figure 1C provides two images of transverse sections of TA of WT and TG animals, with damaged fibers stained by Evans Blue dye 5 days after the injury.
  • Figures 1G-1J illustrate VP16-PPAR5 transgenic animals that exhibit accelerated muscle regeneration after acute injury. All error bars are SEM. *P ⁇ 0.05; **P ⁇ 0.01;
  • Figure 1H illustrates the average number of regenerating fibers per field.
  • Figures 2A-E illustrate that PPAR5 activation promotes a temporal shift in gene expression profile of the regenerative process. *P ⁇ 0.05. All error bars are SEM.
  • Figure 2B shows the relative expression of regeneration markers in TG.
  • Figure 2E is a bar graph showing the Myh8 mRNA level 5 days post injury (n>5).
  • Figures 3A-3G illustrate that PPAR5 regulates FGFla to promote micro- vascularization. *P ⁇ 0.05; **P ⁇ 0.01. All error bars are SEM.
  • Figure 3A provides immunofluorescence staining for CD31 on transverse sections of uninjured TA from WT and TG animals.
  • Figure 3D provides a Western blot for FGF1.
  • Figure 3G provides luciferase reporter assays of FGFla promoter co- transfected with PPAR5 with or without the ligand, GW501516.
  • Figures 4A-4E illustrate that the skeletal muscle specific activation of PPAR5 increases the quiescent satellite cell pool. All error bars are SEM. *P ⁇ 0.05; **P ⁇ 0.01.
  • Figure 4A provides digital images of isolated myofibers from lateral gastrocnemius of 8- week-old nestin reporter mice with or without VP16-PPAR5 transgene.
  • Figure 4D is a bar graph showing VP 16 mRNA levels in whole TA or satellite cells (SC) from WT and TG.
  • Figure 4E is a bar graph showing PPAR5 mRNA levels in whole TA or satellite cells (SC) from WT and TG.
  • Figures 5A-5E illustrate that acute pharmacological activation of PPAR5 confers regenerative advantage. *P ⁇ 0.05; **P ⁇ 0.01; ***P ⁇ 0.001. All error bars are SEM.
  • Figure 5B provides digital images of transverse TA sections showing Evans Blue dye uptake 5 days after the injury.
  • Figures 6A-6E show VP16-PPAR5 transgenic animals exhibit accelerated muscle regeneration after the acute injury. All error bars are SEM.
  • Figure 6A shows werum creatine kinase levels in wildtpe and VP16-PPAR5 transgenic animals.
  • Figure 6B shows transverse sections of TA of WT and TG animals. Staining of damaged fibers by Evans Blue dye 5 days after the injury.
  • Figure 7A shows transverse sections of TA of WT and TG animals. Staining of damaged fibers by Evans Blue 3 days after the injury.
  • Figure 7C shows post injury temporal gene expression profiles of inflammatory markers TNFcc.
  • Figure 7D shows induction of VEGFa in TA muscle, as measured by Western Blot, in TG animals.
  • FIG. 7E shows quantification of TNFa Western Blot.
  • Peroxisome proliferator- activated receptor delta also known as peroxisome proliferator- activated receptor beta (PPARP) or as NR1C2 (nuclear receptor subfamily 1, group C, member 2), refers to a nuclear receptor protein that function as a transcription factor regulating the expression of genes.
  • Ligands of PPAR5 can promote myoblast proliferation after injury, such as injury to skeletal muscle.
  • PPAR5 (OMIM 600409) sequences are publically available, for example from GenBank® sequence database (e.g., accession numbers NP_001165289.1 (human, protein) NP_035275 (mouse, protein), NM_001171818 (human, nucleic acid) and NM_011145 (mouse, nucleic acid)).
  • PPAR5 agonist refers to substances that increase the activity of PPAR5. Substances can be tested for their PPAR5 agonist activity by contacting the substance with cells expressing PPAR5, detecting their binding with PPAR5 and then detecting signals that serve as the indicator of the activation of PPAR5.
  • modulating the activity of PPAR5 is useful in the treatment of diseases, developmental delays, and symptoms related to mitochondrial dysfunction.
  • aliphatic refers to a saturated or unsaturated linear or branched
  • heteroaliphatic means a saturated or unsaturated linear or branched hydrocarbon group containing one or more heteroatoms, and encompasses, for example, heteroalkyl, heteroalkenyl, and heteroalkynyl groups.
  • alkyl used alone or as part of a larger moiety, such as “alkoxy”,
  • haloalkyl means saturated aliphatic straight- chain or branched monovalent hydrocarbon radical. Unless otherwise specified, an alkyl group typically has 1 to 4 carbon atoms, i.e., Ci-C 4 -alkyl. As used herein, a "Ci-C 4 -alkyl” group is means a radical having from 1 to 4 carbon atoms in a linear or branched
  • alkenyl used alone or as part of a larger moiety, such as “alkenoxy”,
  • cycloalkenyl means an unsaturated aliphatic straight-chain or branched monovalent hydrocarbon radical having one or more carbon-carbon double bonds.
  • alkynyl used alone or as part of a larger moiety, such as “alkynoxy”, “haloalkynyl”, and the like, means an unsaturated aliphatic straight-chain or branched monovalent hydrocarbon radical having one or more carbon-carbon triple bonds.
  • Alkylsulfonyl refers to a radical— S(0) 2 R xx where R xx is an alkyl or cycloalkyl group as defined herein. Representative examples include, but are not limited to,
  • Alkoxy means an alkyl radical attached through an oxygen linking atom, represented by -O-alkyl.
  • -O-alkyl For example, "Ci-C3-alkoxy” includes methoxy, ethoxy, propoxy, and butoxy.
  • haloalkyl and “haloalkoxy” mean alkyl or alkoxy, as the case may be, substituted with one or more halogen atoms.
  • Amino refers to the radical -NH 2 .
  • Amide refers to -C(0)-NH-R w , wherein R w is hydrogen, alkyl, aryl, alkylaryl or hydrogen.
  • Carboxyl refers to the radical— C(0)OH.
  • Carboxyl ester refers to the radical— C(0)OR v , wherein R v is hydrogen, alkyl, aryl, or alkylaryl.
  • R v is hydrogen, alkyl, aryl, or alkylaryl.
  • carboxyl bioisostere is a term familiar to medicinal chemists (see for example "The Organic Chemistry of Drug Design and Drug Action", by Richard B.
  • halogen means fluorine or fluoro (F), chlorine or chloro (CI), bromine or bromo (Br), or iodine or iodo (I).
  • ring used herein means a cyclic group, which includes cycloalkyl, heterocycloaklyl, aryl, and heteroaryl, each of which can be monocyclic, bicyclic (e.g. , a bridged bicyclic ring), polycyclic (e.g. , tricyclic), or fused.
  • aryl group means an aromatic hydrocarbon ring system having six to fourteen carbon ring atoms.
  • aryl may be used interchangeably with the terms “aryl ring”, “aromatic ring”, “aryl group”, and “aromatic group”.
  • An aryl group typically has six to fourteen ring atoms.
  • An “aryl group” also includes an aromatic ring fused to a non- aromatic carbocylic ring. Examples of aryl groups include phenyl, naphthyl, anthracenyl, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, fluorenyl, indanyl, indenyl and the like.
  • a “substituted aryl group” is substituted at any one or more substitutable ring atom, which is a ring carbon atom bonded to a hydrogen.
  • “Arylene” is a bivalent aryl group, i.e. , having two point of attachment to the remainder of the molecule.
  • cycloalkyl and "cycloaliphatic” refer to a 3 - 12 membered saturated or unsaturated cyclic hydrocarbon radical. It can be monocyclic, bicyclic (e.g. , a bridged bicyclic ring), polycyclic (e.g. , tricyclic), or fused.
  • monocyclic C 3 -C 6 - cycloalkyl means a radical having from 3 to 6 carbon atoms arranged in a monocyclic ring.
  • a C 3 -C 6 -cycloalkyl includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • Cycloalkylene is a bivalent cycloalkyl group, i.e. , having two point of attachment to the remainder of the molecule.
  • Heterocycloalkyl means a saturated or unsaturated non-aromatic 3 to 12 membered ring radical optionally containing one or more double bonds. It can be monocyclic, bicyclic (e.g. , a bridged bicyclic ring), tricyclic, or fused.
  • the heterocycloalkyl contains 1 to 4 heteroatoms, which may be the same or different, selected from N, O or S.
  • heterocycloalkyl ring optionally contains one or more double bonds and/or is optionally fused with one or more non-aromatic carbocyclic rings, aromatic rings (e.g. , phenyl ring) or heteroaryl rings.
  • "5- or 6-membered monocyclic heterocycloalkyl” means a radical having from 5 or 6 atoms (including 1 to 3 heteroatoms) arranged in a monocyclic ring. Examples of heterocycloalkyl include, but are not limited to, morpholinyl, thiomorpholinyl,
  • pyrrolidinonyl pyrrolidinyl, piperidinyl, piperazinyl, hydantoinyl, valerolactamyl, dihydroimidazole, dihydrofuranyl, dihydropyranyl, dihydropyridinyl, dihydropyrimidinyl, dihydrothienyl, dihydrothiophenyl, dihydrothiopyranyl, tetrahydroimidazole,
  • Heterocycloalkylene is a bivalent heterocycloalkyl group, i.e., having two point of attachment to the remainder of the molecule.
  • heteroaryl "heteroaromatic”, “heteroaryl ring”, “heteroaryl group”,
  • hetero aromatic ring and “heteroaromatic group”, are used interchangeably herein.
  • Heteroaryl when used alone or as part of a larger moiety as in “heteroaralkyl” or
  • hetero arylalkoxy refers to aromatic ring groups having five to fourteen ring atoms selected from carbon and at least one (typically 1 to 4, more typically 1 or 2) heteroatoms (e.g., oxygen, nitrogen or sulfur).
  • heteroaryl includes monocyclic rings and polycyclic rings in which a monocyclic heteroaromatic ring is fused to one or more other aromatic or
  • Heteroarylene is a bivalent heteroaryl group, i.e. , having two point of attachment to the remainder of the molecule.
  • “Monocyclic 5- or 6-membered heteroaryl” means a monocyclic aromatic ring system having five or six ring atoms selected from carbon and at least one (typically 1 to 3, more typically 1 or 2) heteroatoms (e.g., oxygen, nitrogen or sulfur).
  • Examples of monocyclic 5-6 membered heteroaryl groups include furanyl (e.g.
  • 2-furanyl, 3-furanyl imidazolyl (e.g., N- imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), isoxazolyl (e.g., 3-isoxazolyl, 4- isoxazolyl, 5-isoxazolyl), oxadiazolyl (e.g., 2-oxadiazolyl, 5-oxadiazolyl), oxazolyl (e.g., 2- oxazolyl, 4-oxazolyl, 5-oxazolyl), pyrazolyl (e.g. , 3-pyrazolyl, 4-pyrazolyl), pyrrolyl (e.g.
  • polycyclic aromatic heteroaryl groups include carbazolyl, benzimidazolyl, benzothienyl, benzofuranyl, isobenzofuranyl, indolyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, indazolyl, isoindolyl, acridinyl, or benzisoxazolyl.
  • a "substituted heteroaryl group” is substituted at any one or more substitutable ring atom, which is a ring carbon or ring nitrogen atom bonded to a hydrogen.
  • fused refers to any combination of two or more cycloalkyl, heterocycloalkyl, aryl, and/or heteroaryl rings that share two adjacent ring atoms.
  • bridged refers to two carbocyclic refers to any combination of two cycloalkyl or heterocycloalkyl rings that share three or more adjacent ring atoms.
  • a non-hydrogen substituent is in the place of a hydrogen substituent on a carbon, sulfur or nitrogen of the substituent.
  • a substituted alkyl is an alkyl wherein at least one non-hydrogen substituent is in the place of a hydrogen substituent on the alkyl substituent.
  • monofluoroalkyl is alkyl substituted with a fluoro substituent
  • difluoroalkyl is alkyl substituted with two fluoro substituents. It should be recognized that if there is more than one substitution on a substituent, each non-hydrogen substituent can be identical or different (unless otherwise stated).
  • the substituent can be either (1) not substituted, or (2) substituted.
  • a list of groups are collectively described as being optionally substituted by one or more of a list of substituents, the list can include: (1) unsubstitutable groups, (2) substitutable groups that are not substituted by the optional substituents, and/or (3) substitutable groups that are substituted by one or more of the optional substituents.
  • a group is described as being optionally substituted with up to a particular number of non-hydrogen substituents, that group can be either (1) not substituted; or (2) substituted by up to that particular number of non-hydrogen substituents or by up to the maximum number of substitutable positions on the substituent, whichever is less.
  • a group is described as a heteroaryl optionally substituted with up to 3 non-hydrogen substituents, then any heteroaryl with less than 3 substitutable positions would be optionally substituted by up to only as many non-hydrogen substituents as the heteroaryl has
  • R a and R b are each independently selected from -H and (Ci-C 6 )alkyl, optionally substituted with 1 to 3 substituents independently selected from halogen, hydroxy, -NR g R h and (Ci-C3)alkoxy;
  • R c is -H or (Ci-C 6 )alkyl, optionally substituted with 1 to 3 substituents independently selected from halogen, -NR g R h , hydroxy and (Cp C 3 )alkoxy;
  • R d is -H or (Ci-C 6 )alkyl, optionally substituted with 1 to 3 substituents independently selected from halogen, -NR g R h , hydroxy and
  • suitable substituents for substituted alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups include alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, and halogen.
  • Stereoisomers are compounds that differ only in their spatial arrangement.
  • a disclosed compound is named or depicted by structure without indicating stereochemistry, it is understood that the name or the structure encompasses all possible stereoisomers, geometric isomers, or a combination thereof.
  • geometric isomeric purity of the named or depicted geometric isomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% pure by weight.
  • Geometric isomeric purity is determined by dividing the weight of the named or depicted geometric isomer in the mixture by the total weight of all of the geomeric isomers in the mixture.
  • Racemic mixture means 50% of one enantiomer and 50% of is corresponding enantiomer.
  • a compound with one chiral center is named or depicted without indicating the stereochemistry of the chiral center, it is understood that the name or structure encompasses both possible enantiomeric forms (e.g., both enantiomerically-pure, enantiomerically-enriched or racemic ) of the compound.
  • Enantiomeric and diastereomeric mixtures can be resolved into their component enantiomers or stereoisomers by well-known methods, such as chiral -phase gas
  • Enantiomers and diastereomers also can be obtained from diastereomerically- or
  • a compound When a compound is designated by a name or structure that indicates a single enantiomer, unless indicated otherwise, the compound is at least 60%, 70%, 80%, 90%, 99% or 99.9% optically pure (also referred to as "enantiomerically pure").
  • Optical purity is the weight in the mixture of the named or depicted enantiomer divided by the total weight in the mixture of both enantiomers.
  • stereochemistry of a disclosed compound is named or depicted by structure, and the named or depicted structure encompasses more than one stereoisomer (e.g. , as in a diastereomeric pair), it is to be understood that one of the encompassed stereoisomers or any mixture of the encompassed stereoisomers are included. It is to be further understood that the stereoisomeric purity of the named or depicted stereoisomers at least 60%, 70%, 80%, 90%, 99% or 99.9% by weight. The stereoisomeric purity in this case is determined by dividing the total weight in the mixture of the stereoisomers encompassed by the name or structure by the total weight in the mixture of all of the stereoisomers.
  • Suitable pharmaceutically acceptable salts of the compounds disclosed herein include salts of inorganic acids (such as hydrochloric acid, hydrobromic, phosphoric, nitric, and sulfuric acids) and of organic acids (such as, e.g. , acetic acid, benzenesulfonic, benzoic, methanesulfonic, and /?-toluenesulfonic acids).
  • inorganic acids such as hydrochloric acid, hydrobromic, phosphoric, nitric, and sulfuric acids
  • organic acids such as, e.g. , acetic acid, benzenesulfonic, benzoic, methanesulfonic, and /?-toluenesulfonic acids.
  • Compounds of the present teachings with acidic groups such as carboxylic acids can form pharmaceutically acceptable salts with pharmaceutically acceptable base(s).
  • Suitable pharmaceutically acceptable basic salts include ammonium salts, alkali metal salts (such as sodium
  • the term "pharmaceutically-acceptable salt” refers to pharmaceutical salts that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, and allergic response, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically-acceptable salts are well known in the art. For example, S. M. Berge, et al. describes pharmacologically acceptable salts in J. Pharm. Sci., 1977, 66: 1-19.
  • the neutral forms of the compounds of the invention are regenerated from their corresponding salts by contacting the salt with a base or acid and isolating the parent compound in the conventional manner.
  • the parent form of the compound may differ from the various salt forms in certain physical properties, such as solubility in polar solvents.
  • the neutral forms of compounds disclosed herein also are included in the invention.
  • administer refers to methods that may be used to enable delivery of compositions to the desired site of biological action. These methods include, but are not limited to, intraarticular (in the joints), intravenous, intramuscular, intratumoral, intradermal, intraperitoneal, subcutaneous, orally, topically, intrathecally, inhalationally, transdermally, rectally, and the like.
  • Administration techniques that can be employed with the agents and methods described herein are found in e.g., Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa.
  • co-administration are meant to encompass administration of two or more therapeutic agents to a single subject, and are intended to include treatment regimens in which the agents are administered by the same or different route of administration or at the same or different times.
  • the one or more compounds described herein will be co- administered with other agents.
  • These terms encompass administration of two or more agents to the subject so that both agents and/or their metabolites are present in the subject at the same time. They include simultaneous administration in separate compositions,
  • the compounds described herein and the other agent(s) are administered in a single composition.
  • the compounds described herein and the other agent(s) are admixed in the composition.
  • an effective amount of a compound taught herein varies depending upon various factors, such as the given drug or compound, the pharmaceutical formulation, the route of administration, the type of disease or disorder, the identity of the subject or host being treated, and the like, but can nevertheless be routinely determined by one skilled in the art.
  • An effective amount of a compound of the present teachings may be readily determined by one of ordinary skill by routine methods known in the art.
  • a therapeutically effective amount means an amount when administered to the subject which results in beneficial or desired results, including clinical results, e.g., inhibits, suppresses or reduces the symptoms of the condition being treated in the subject as compared to a control.
  • a therapeutically effective amount can be given in unit dosage form (e.g. , 1 mg to about 50 g per day, altnernatively from 10 mg to about 5 grams per day; and in another alternatively from 10 mg to 1 gram per day).
  • a "subject” is a mammal, preferably a human, but can also be an animal in need of veterinary treatment, e.g. , companion animals (e.g. , dogs, cats, and the like), farm animals (e.g. , cows, sheep, pigs, horses, and the like) and laboratory animals (e.g. , rats, mice, guinea pigs, and the like).
  • companion animals e.g. , dogs, cats, and the like
  • farm animals e.g. , cows, sheep, pigs, horses, and the like
  • laboratory animals e.g. , rats, mice, guinea pigs, and the like.
  • “Pharmaceutically acceptable excipient” and “pharmaceutically acceptable carrier” refer to a substance that aids the formulation and/or administration of an active agent to and/or absorption by a subject and can be included in the compositions of the present disclosure without causing a significant adverse toxicological effect on the subject.
  • Non- limiting examples of pharmaceutically acceptable excipients include water, NaCl, normal saline solutions, lactated Ringer's, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors, salt solutions (such as Ringer's solution), alcohols, oils, gelatins, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethycellulose, polyvinyl pyrrolidine, and colors, and the like.
  • Such preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with or interfere with the activity of the compounds provided herein.
  • auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with or interfere with the activity of the compounds provided herein.
  • auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with or interfere with the activity of the compounds provided herein.
  • auxiliary agents such
  • PPAR5 agonists compounds having PPAR5 agonist activity
  • PPAR5 agonists Compounds with PPAR5 agonist activity (also referred to herein as "PPAR5 agonists”) can be used in any of the methods disclosed herein, provided that the PPAR5 agonist is not a compound having the formula:
  • ring A is selected from a cycloalkylene, heterocycloalkylene, arylene or
  • ring B is selected from an aryl, heteroaryl, cycloalkyl, heterocycloalkyl,
  • heterocycloalkylene arylene or heteroarylene
  • each R independently is selected from deuterium, halogen, aryl, heteroaryl, aliphatic, heteroaliphatic, cycloaliphatic, N0 2 , OH, amino, amide, aminosulfonyl, carboxyl, carboxyl ester, alkylsulfonyl, S0 3 H, or acyl;
  • each R 22 independently is selected from deuterium, halogen, aryl, heteroaryl, aliphatic,
  • n is from 0 to 5;
  • n is from 0 to 4.
  • X is O, NR 30 , sulfonyl, or S;
  • R 30 is selected from H or aliphatic, aryl, or cycloaliphatic
  • L 5 is selected from a bond, aliphatic, heteroaliphatic, arylene, heteroarylene, cycloalkylene, heterocycloalkylene or -L 3 N(L 4 R 3 )L 3 -; L is selected from a bond, aliphatic, heteroaliphatic, arylene, heteroarylene,
  • R" J are each independently selected from H, deuterium, halogen, aliphatic, alkyl, -C(0)OR 25 or -C(0)NR 25 R 26 ;
  • R 25 and R 26 are each independently hydrogen, aliphatic or alkyl
  • Z is selected from R 1 L 1 C(0)- or a carboxyl bioisostere
  • L 1 is a bond or -NR 30 -;
  • R 1 is hydrogen, aliphatic, -OR 1A , -NR 1A R 1B , -C(0)R 1A , -S(0) 2 R 1A , -C(0)OR 1A , - S(0) 2 NR 1A R 1B or -C(0)NR 1A R 1B ;
  • R 1A , R 1B are each independently hydrogen, aliphatic or alkyl
  • L is selected from a bond, aliphatic, -C(O)-, alkylC(O)-, -C(0)alkyl-, or sulfonyl;
  • L 4 is selected from a bond, aliphatic, heteroaliphatic, arylene, heteroarylene,
  • R 3 is selected from -OH, -OR 3A , -NR 3A R 3B , -C(0)R 3A , -S(0)2R 3A , -C(0)OR 3A , - S(0) 2 NR 3A R 3B , -C(0)NR 3A R 3B , aliphatic, heteroaliphatic, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or R can be joined with an atom of ring B to form a fused ring system or may be joined with an atom of L to form a heterocyclic ring system; and
  • R , R are each independently hydrogen, aliphatic or alkyl.
  • the PPAR5 agonist is a compound of Formula (I):
  • Ar is phenyl, which is optionally substituted with from one to five R substituents independently selected from the group consisting of halogen, (Ci-Cg)alkyl, halo(Ci-Cg)alkyl, and -OR 2 ;
  • Ar is phenyl, which is optionally substituted with from one to four R substituents independently selected from the group consisting of halogen, (Ci-Cg)alkyl, halo(Ci-Cg)alkyl, and -OR 2 ;
  • L is a member selected from the group consisting of -CH 2 S- and -CH 2 0-; K is a member selected from the group consisting of a covalent bond and -OCH 2 - Z is C0 2 R 6 ;
  • R 1 is selected from the group consisting of H and (Ci-C8)alkyl
  • each R 2 and R 3 is a member independently selected from the group consisting of H, (C C 8 )alkyl, halo(C C 8 )alkyl,— X 3 OR 9 , aryl, aryl(C C 4 )alkyl, and heteroaryl, or optionally, if both present on the same substituent, may be joined together to form a three- to eight-membered ring system;
  • R 6 is a member selected from the group consisting of H, (Ci-C 8 )alkyl, halo(Ci- C 8 )alkyl,— X 4 OR 2 ,— X 4 NR 2 R 3 , (C 2 -C 8 )alkenyl, (C 3 -C 7 )cycloalkyl, heterocyclyl, aryl (C C 4 )alkyl; and aryl(C 2 -C 8 )alkenyl;
  • R 9 is a member selected from the group consisting of H, (Ci-C 8 )alkyl, halo(Ci- C 8 )alkyl, aryl, aryl(Ci-C 4 )alkyl, and heteroaryl;
  • each X 3 and X 4 is a member independently selected from the group consisting of (Cp C 4 ) alkylene, (C 2 -C 4 )alkenylene, and (C 2 -C4)alkynylene.
  • the compound of Formula (I) has the structure of Formula
  • the PPAR5 agonist is a compound of Formula (II):
  • X represents a COOH (or a hydrolysable ester thereof),
  • X I is O or S, and the depicted bond with a dashed line is a single bond;
  • X represents O, S;
  • R 1 and R 2 independently represent H, CH 3 , OCH 3 or halogen;
  • n 1 or 2;
  • one of Y and Z is N and the other is S or O;
  • y 1 or 2;
  • each R independently represents CF 3 or halogen.
  • the compound of Formula (II) has the structure of Formula
  • the PPAR5 agonist is a compound of Formula (III):
  • A is a saturated or unsaturated hydrocarbon chain having from 3 to 5 atoms, forming five- to seven-membered ring;
  • T is selected from the group consisting of -C(0)OH, -C(0)NH 2 , and tetrazole;
  • G 1 is selected from the group consisting of -(CR'R 2 ) ⁇ , -ZiCR 1 ⁇ 2 ) ⁇ , -(CR ⁇ n Z-, -(CR ⁇ CR ⁇ -;
  • Z is O, S or NR
  • n 0, 1, or 2;
  • r and s are independently 0 or 1 ;
  • R 1 and R 2" are independently selected from the group consisting of hydrogen, halo, optionally substituted lower alkyl, optionally substituted lower heteroalkyl, optionally substituted lower alkoxy, and lower perhaloalkyl or together may form an optionally substituted cycloalkyl; 1 2 3
  • X X ⁇ and X J are independently selected from the group consisting of hydrogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, halogen, perhaloalkyl, hydroxy, optionally substituted lower alkoxy, nitro, cyano, and NH 2 ;
  • G 2 is selected from the group consisting of a saturated or unsaturated heterocycloalkyl linker, optionally substituted with X 4 and X5;
  • X 4 and X 5 are independently selected from the group consisting of hydrogen, optionally substituted lower alkyl, halogen, lower perhaloalkyl, hydroxy, optionally substituted lower alkoxy, nitro, cyano, NH 2 , and C0 2 R, or X 4 and X5 together may form a carbocycle;
  • R is selected from the group consisting of optionally substituted lower alkyl and hydrogen
  • n 0, 1, or 2;
  • R 3 and R 4 are independently selected from the group consisting of hydrogen, optionally substituted lower alkyl, optionally substituted lower alkoxy, optionally substituted aryl, lower perhaloalkyl, cyano, and nitro;
  • R 5 and R 6 are independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, and optionally substituted cycloheteroalkyl.
  • the compound of Formula (III) has the structure of Formula
  • the compound of Formula (III) has the structure of Formula
  • Such methods can include contacting a PPAR5 protein with an effective amount of a compound or composition provided herein, thereby activating PPAR5.
  • the contacting is performed in vitro. In other embodiments, the contacting is performed within a subject, such as a human subject, for example by administering a PPAR agonist disclosed herein to the subject. In some embodiments, the compound or composition is administered to a healthy subject. In some embodiments, the subject is a sedentary or immobilized subject. In other embodiments, the subject is an exercising subject, such as one who exercises for at least 20 minutes, at least 30 mintues, at least 45 mintures, or at least 60 minutes, at least 2, at least 3, or at least 4 days per week. In some embodiments, a healthy subject is also an exercising subject.
  • contacting a PPAR5 protein in vitro or in vivo with an effective amount of one or more compounds or compositions provided herein increases PPAR5 activity by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 100%, at least 200%, at least 300%, at least 400%, or even at least 500%, for example as compared to an amount of PPAR5 activity in the absence of the compound/composition.
  • Methods of measuring PPAR5 activity are known, and specific examples are provided herein (e.g., measuring expression of PPAR5 at the protein or nucleic acid level, measuring Beta oxidation levels, creatine kinase levels, pentose phosphate shunt in liver, blood glucose levels and methods provided in Wang et al., PLos Biol. 2(10):e294, 2004 and Lee et al., PNAS 103:3444-9, 2006).
  • the subject recovers from acute injury following
  • activating PPAR5 within the subject by administration of a PPAR5 agonist increases or maintains muscle mass or muscle tone (such as a skeletal or cardiac muscle) in the subject (such as in a healthy subject or a sedentary subject).
  • a PPAR5 agonist or composition containing a PPAR5 agonist
  • increases or maintains muscle mass or muscle tone such as a skeletal or cardiac muscle
  • muscle tone such as a skeletal or cardiac muscle
  • activating PPAR5 within the subject can increase muscle mass, muscle tone, or both, in the subject.
  • administering an effective amount of one or more PPAR5 agonist compounds or compositions provided herein increases muscle mass, muscle tone, or both, by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 100%, at least 200%, at least 300%, at least 400%, or even at least 500%, for example as compared to an amount of PPAR5 activity in the absence of the
  • activating PPAR5 within the subject maintains muscle mass, muscle tone, or both, in the subject.
  • administering an effective amount of one or more PPAR5 agonist compounds or compositions maintains muscle mass, muscle tone, or both, such that the amount of muscle mass, muscle tone or both, does not change by more than 1%, for example no more than 2%, no more than 3%, no more than 4%, no more than 5%, no more than 6%, no more than 7%, no more than 8%, no more than 9%, no more than 10%, or no more than 15%, for example as compared to an amount of muscle mass, muscle tone, or both in the absence of the compound/composition.
  • Methods of measuring muscle mass and muscle tone are known, and specific examples are provided herein (e.g. , see methods provided in WO 2009/086526).
  • PPAR5 agonists and compositions containing such can be used to increase or maintain muscle mass or muscle tone (or both) in a subject.
  • the disclosed PPAR agonists and compositions containing such can be used to increase or maintain muscle mass or muscle tone (or both) in a subject following an injury, following a period of immobilization (for example confinement to a bed or wheelchair) or immobilization of a body part (for example immobilization of an appendage or joint due to a broken bone, joint replacement, tendon tear, surgery, and the like), which events can result in a loss of muscle mass and/or muscle tone.
  • the method includes administering to the subject a therapeutically effective amount of one or more compounds provided herein.
  • the subject is a sedentary or immobilized subject. In other embodiments, the subject is an exercising subject. Methods of treating a PPAR5-related disease or condition in a subject in need thereof also are provided. The methods can include administering to the subject a therapeutically effective amount of one or more compounds or compositions provided herein.
  • the ⁇ -related disease is a mitochondrial disease.
  • mitochondrial diseases include, but are not limited to, Alpers's Disease, CPEO- Chronic progressive external ophthalmoplegia , Kearns-Sayra Syndrome (KSS), Leber Hereditary Optic Neuropathy (LHON), MELAS-Mitochondrial myopathy,
  • encephalomyopathy lactic acidosis, and stroke-like episodes
  • MERRF-Myoclonic epilepsy and ragged-red fiber disease
  • NARP-neurogenic muscle weakness ataxia
  • retinitis pigmentosa Pearson Syndrome.
  • the PPAR5-related disease is a vascular disease (such as a cardiovascular disease or any disease that would benefit from increasing vascularization in tissues exhibiting impaired or inadequate blood flow).
  • the PPAR5- related disease is a muscular disease, such as a muscular dystrophy. Examples of muscular dystrophy include but are not limited to Duchenne muscular dystrophy, Becker muscular dystrophy, limb-girdle muscular dystrophy, congenital muscular dystrophy,
  • facioscapulohumeral muscular dystrophy myotonic muscular dystrophy, oculopharyngeal muscular dystrophy, distal muscular dystrophy, and Emery-Dreifuss muscular dystrophy.
  • the PPAR5-related disease or condition is a demyelinating disease, such as multiple sclerosis, Charcot-Marie-Tooth disease, Pelizaeus-Merzbacher disease, encephalomyelitis, neuromyelitis optica, adrenoleukodystrophy, or Guillian-Barre syndrome.
  • demyelinating disease such as multiple sclerosis, Charcot-Marie-Tooth disease, Pelizaeus-Merzbacher disease, encephalomyelitis, neuromyelitis optica, adrenoleukodystrophy, or Guillian-Barre syndrome.
  • the PPAR5-related disease is a muscle structure disorder.
  • a muscle structure disorders include, but are not limited to, Bethlem myopathy, central core disease, congenital fiber type disproportion, distal muscular dystrophy (MD), Duchenne & Becker MD, Emery- Dreifuss MD, facioscapulohumeral MD, hyaline body myopathy, limb-girdle MD, a muscle sodium channel disorders, myotonic chondrodystrophy, myotonic dystrophy, myotubular myopathy, nemaline body disease, oculopharyngeal MD, and stress urinary incontinence.
  • MD distal muscular dystrophy
  • Duchenne & Becker MD Emery- Dreifuss MD
  • facioscapulohumeral MD hyaline body myopathy
  • limb-girdle MD a muscle sodium channel disorders
  • myotonic chondrodystrophy myotonic dystrophy
  • the PPAR5-related disease is a neuronal activation disorder
  • neuronal activation disorders include, but are not limited to, amyotrophic lateral sclerosis, Charcot-Marie-Tooth disease, Guillain-Barre syndrome, Lambert-Eaton syndrome, multiple sclerosis, myasthenia gravis, nerve lesion, peripheral neuropathy, spinal muscular atrophy, tardy ulnar nerve palsy, and toxic myoneural disorder.
  • the PPAR5-related disease is a muscle fatigue disorder.
  • muscle fatigue disorders include, but are not limited to chronic fatigue syndrome, diabetes (type I or II), glycogen storage disease, fibromyalgia, Friedreich's ataxia, intermittent claudication, lipid storage myopathy, MELAS, mucopolysaccharidosis, Pompe disease, and thyrotoxic myopathy.
  • the ⁇ -related disease is a muscle mass disorder.
  • muscle mass disorders include, but are not limited to, cachexia, cartilage degeneration, cerebral palsy, compartment syndrome, critical illness myopathy, inclusion body myositis, muscular atrophy (disuse), sarcopenia, steroid myopathy, and systemic lupus erythematosus.
  • the ⁇ -related disease is a beta oxidation disease.
  • beta oxidation diseases include, but are not limited to, systemic carnitine transporter, carnitine palmitoyltransferase (CPT) II deficiency, very long- chain acyl- CoA dehydrogenase (LCHAD or VLCAD) deficiency, trifunctional enzyme deficiency, medium - chain acyl - CoA dehydrogenase (MCAD) deficiency, short - chain acyl- CoA dehydrogenase (SCAD) deficiency, and riboflavin - responsive disorders of ⁇ -oxidation (RR -MADD).
  • CPT carnitine palmitoyltransferase
  • LCHAD or VLCAD very long- chain acyl- CoA dehydrogenase
  • MCAD medium - chain acyl - CoA dehydrogenase
  • SCAD short - chain acyl- CoA dehydrogenase
  • RR -MADD ribofla
  • the PPAR5-related disease is a vascular disease.
  • vascular diseases include, but are not limited to, peripheral vascular insufficiency, peripheral vascular disease, intermittent claudication, peripheral vascular disease (PVD), peripheral artery disease (PAD), peripheral artery occlusive disease (PAOD), and peripheral obliterative arteriopathy.
  • the PPAR5-related disease is an ocular vascular disease.
  • ocular vascular diseases include, but are not limited to, age-related macular degeneration (AMD), stargardt disease, hypertensive retinopathy, diabetic retinopathy, retinopathy , macular degeneration, retinal haemorrhage, and glaucoma.
  • AMD age-related macular degeneration
  • stargardt disease hypertensive retinopathy
  • diabetic retinopathy diabetic retinopathy
  • retinopathy macular degeneration
  • retinal haemorrhage and glaucoma.
  • the PPAR5-related disease is a muscular eye disease.
  • muscular eye diseases include, but are not limited to, strabismus (crossed eye/wandering eye/walleye ophthalmoparesis), progressive external ophthalmoplegia, esotropia, exotropia, a disorder of refraction and accommodation, hypermetropia, myopia, astigmatism, anisometropia, presbyopia, a disorders of accommodation, or
  • the PPAR5-related disease is a metabolic disease selected from hyperlipidemia, dyslipidemia, hypercholesterolemia, hypertriglyceridemia, HDL hypocholesterolemia, LDL hypercholesterolemia and/or HLD non-cholesterolemia, VLDL hyperproteinemia, dyslipoproteinemia, apolipoprotein A-I hypoproteinemia, atherosclerosis, disease of arterial sclerosis, disease of cardiovascular systems, cerebrovascular disease, peripheral circulatory disease, metabolic syndrome, syndrome X, obesity, diabetes (type I or II), hyperglycemia, insulin resistance, impaired glucose tolerance, hyperinsulinism, diabetic complication, cardiac insufficiency, cardiac infarction, cardiomyopathy, hypertension, Nonalcoholic fatty liver disease (NAFLD), Nonalcoholic steatohepatitis (NASH), thrombus, Alzheimer disease, neurodegenerative disease, demyelinating disease, multiple sclerosis, adrenal leukodystrophy, dermatitis, psoriasis, acne,
  • NASH Non
  • the PPAR5-related disease is a cancer selected from a cancer of the colon, large intestine, skin, breast, prostate, ovary, or lung.
  • compositions that include one or more PPAR5 agonists, and typically at least one additional substance, such as an excipient, a known therapeutic other than those of the present disclosure, and combinations thereof.
  • a PPAR5 agonist can be used in combination with other agents known to have beneficial, additive or synergistic activity with the PPAR5 agonists.
  • disclosed compounds can be administered alone or in combination with: one or more other PPAR5 agonists, such as a thiazolidinedione, including rosiglitazone, pioglitazone, troglitazone, and combinations thereof, or a sulfonylurea agent or a pharmaceutically acceptable salt thereof, such as tolbutamide, tolazamide, glipizide, carbutamide, glisoxepide, glisentide, glibornuride, glibenclamide, gliquidone glimepiride, gliclazide and the pharmaceutically acceptable salts of these compounds, or muraglitazar, farglitazar, naveglitazar, netoglitazone, rivoglitazone, K- 111, GW-677954, (-)-Halofenate, acid, arachidonic acid, clofbrate, gemfibrozil, fenofibrate, ciprofibrate, be
  • disclosed compounds may be administered in combination with dexamphetamine, amphetamine, mazindole, or phentermine; and administered in
  • the particular mode of administration and the dosage regimen will be selected by the attending clinician, taking into account the particulars of the case (e.g. the subject, the disease, the disease state involved, the particular treatment, and whether the treatment is prophylactic). Treatment can involve daily or multi-daily or less than daily (such as weekly or monthly etc.) doses over a period of a few days to months, or even years. However, a person of ordinary skill in the art would immediately recognize appropriate and/or equivalent doses looking at dosages of approved compositions for treating a PPAR5 related disease using the disclosed PPAR5 agonists for guidance.
  • Skeletal muscle relies on the resident progenitor cells, the satellite cells, for postnatal growth and regeneration. Therefore, maintaining an adequate number and proper function of satellite cells is critical for muscle to appropriately response to damage. While endurance exercise promotes adaptive responses in the muscle, including an increase in the satellite cell number, it is not known whether transcriptionally directed "endurance exercise training" has similar effects.
  • mice harboring constitutively active PPAR5 in skeletal muscle displayed an accelerated regenerative process in muscle after an acute injury. Gene expression analyses showed earlier resolution of the inflammatory response and induction of myogenic markers, indicating that PPAR5 activation induces a temporal shift in the regenerative process.
  • PPAR5 activation induced the expression of FGF1, which is known to be involved in muscle development and regeneration.
  • FGFla isoform which may be responsible for supporting cell proliferation and reestablishment of vasculature to augment the
  • PPAR5 peroxisome proliferator activated receptor ⁇
  • VP16-PPAR5 mice Wang et al, Cell 113: 159-170 (2003) were bred to CB6F1 strain (Jackson Laboratories) and used as heterozygotes in experiments. The non-transgenic littermates served as controls. All experiments were performed when animals were 8 weeks of age.
  • Nestin-GFP mice (Mignone et al, J Comp Neurol 469(3):311-324 (2004)) were kindly provided by Dr. Fred Gage at the Salk Institute for Biological Studies. B. Freeze burn injury
  • TA muscles were injured according to previously published methods with a few modifications (Brack et ah, Science 317(5839):807-810 (2007)).
  • a stainless steel lg weight (Mettler- Toledo) equilibrated to the temperature of dry ice was placed directly on the exposed TA for 10 seconds. Following the thermal injury, incision was closed using
  • Tissues were dehydrated in series of solutions with increasing percentage of ethanol. Dehydrated tissues were cleared in xylene and allowed for paraffin to permeate over night at 60 °C. Tissues were then embedded in plastic molds.
  • Paraffin embedded tissue blocks were sectioned at 7 ⁇ thick on Leica Jung 2500 Microtome. Sections were stained with hematoxylin and counter stained with 1% eosin. Slides were dried and mounted with Entellan mounting media (EMS). Three random non- overlapping fields were photographed for analysis. Regenerating fiber number was measured by counting the number of discernible muscle fibers with centralized myonuclei (Ge et ah, Am J Physiol Cell Physiol 297 (6):C1434- 1444 (2009)). Regenerating fiber cross sectional area (CSA) was measured using Image J software.
  • BrdU 50 mg/kg body weight of BrdU (Sigma) was injected intraperitoneally as solution of 10 mg/mL BrdU in saline. TA muscles were harvested at 7 days after injury and processed for paraffin sections as described above. BrdU incorporation was visualized using the BrdU Labeling and Detection Kit I (Roche) and BrdU+ nuclei were counted and represented as a proportion of total nuclei in a field.
  • cDNAs were diluted 1/40 with ddH 2 0 and used as templates in RT-QPCR reactions with SYBRGreenER qPCR SuperMix detection system (Invitrogen). Samples were prepared in technical triplicates and relative mRNA levels were calculated by using the standard curve methodology and normalized against GAPDH mRNA levels in the same samples.
  • Either whole or partial gastrocnemius muscle was digested in 2% collagenase I (Sigma) in DMEM with 10% FBS for 60 minutes at 37 °C. Muscle tissue was further mechanically digested by triturating with fire polished wide bore Pasteur pipet. Liberated fibers were washed in two changes of PBS with 10%FBS and finally mounted on glass slides with Vectashield mounting media (Vector Labs).
  • Satellite cells were harvested from TA of 8 weeks old animals according to published protocols with some modifications (Day et al. (2007) Nestin-GFP reporter expression defines the quiescent state of skeletal muscle satellite cells.
  • Digested tissues were filtered through 40 micron cell strainer and washed with equal volume of DMEM with 20% horse serum. Cells were spun down at lOOOg for 10 minutes and resuspended in sorting buffer (DMEM with 10% FBS). Cells were separated from larger debris by 20%/60% Percoll gradient (Yablonka-Reuveni Z et al. (1987) Isolation and clonal analysis of satellite cells from chicken pectoralis muscle. Dev Bio 119: 252-259). GFP positive cells were sorted on BD FACSAria II sorter.
  • Muscle specific activation of PPAR5 confers regenerative advantage While it has been shown that the majority of the metabolic genes are down regulated in this model, PPAR5 expression was induced over 2 fold at 2 days after the injury (Warren et al. (2007) Mechanisms of skeletal muscle injury and repair revealed by gene expression studies in mouse models. J Physiol. 582.2: 825-841, Figure 1A). This injury dependent up- regulation of PPAR5 strongly suggested a possible role for PPAR5 during the early part of the regenerative proces s .
  • Freeze burn injury was used to elicit the regenerative program, which has been shown to model the standard course of regenerative response, including satellite cell activation (Karpati and Molnar. "Muscle fibre regeneration in human skeletal muscle diseases.” In: Schiaffino S, Partridge T (eds). Skeletal muscle repair and regeneration. Springer, Dordrecht, 2008). Additionally, since the injury is directly applied to the surface of the muscle, it is highly localized and reproducible.
  • Skeletal muscle regeneration is an intricately orchestrated process involving a variety of cell types.
  • immune cells both neutrophils and macrophages, are necessary for the proper progression of regenerative process (Zacks et al., Muscle Nerve 5:152-161 (1982); Grounds et al., Cell Tissue Res 250:563-569 (1987); Teixeira et al.
  • PPAR5 directs neovascularization via regulation of FGF1 This example describes adaptive responses bestowed by PPAR5 activation in the muscle which may contribute to the observed beneficial effects on regeneration.
  • Increased vasculature is one of the hallmarks of oxidative myofibers, which facilitates introduction of immune cells and also supports increased number of satellite cells.
  • TG animals show increased expression of FGF1 in TA muscle (Figure 3D).
  • TG animals Upon injury, TG animals maintain high expression of FGF1 expression ( Figure 3D).
  • Immunostaining transverse sections of uninjured TA from WT and TG animals revealed 36% increase in the number of CD31+ capillaries per field by PPAR5 activation ( Figures 3A-C).
  • TG animals show increased expression of CD31, which is indicative of increased vascularity (Figures 3E-F).
  • FGF1 has been shown to be expressed in regenerating fibers in chronic disease models and has been implicated in myogenesis and regeneration (Oliver, Growth Factors. 1992;7(2):97- 106, 1992; Saito, 2000, Muscle Nerve. 23(4):490-7) and to increase microvasculature in adipocytes and PPAR5 directly regulates expression of FGFla isoform (Jonker et ah, Nature. 485(7398):391-4, 2012). Therefore, increased vascularity may contribute to the accelerated regenerative process observed in VP16-PPAR5 animals.
  • One of the first events following the injury is the proliferation of muscle resident progenitors, the satellite cells. This example describes results showing that the regenerative advantage observed in TG animals could be due to altered satellite cell homeostasis.
  • Nestin expression was used as a marker of satellite cells, and nestin-GFP;VP16- PPAR5 double transgenic animals were used to genetically label quiescent satellite cells(SCs) in vivo (Mignone et al, J Comp Neurol 469(3):311-324 (2004); Day et al, Dev Biol 304(1 ):246-259 (2007)). Gastrocnemius muscles were enzymatically digested to liberate individual fibers, then mounted for quantification (Figure 4A). While double transgenic animals averaged 1.01 SCs per mm of fiber length, GFP+ animals only had 0.15 SCs per mm, a 6.48 fold higher SC content on VP16- PPAR5 muscle fiber ( Figure 4B).
  • Satellite cell activity was measured as myoblast proliferation elicited by the freeze burn injury in vivo.
  • BrdU was intraperitoneally injected at 12 hrs, 24 hrs and 2 days after the injury and the muscles were harvested 7 days after the injury to calculate the ratio of BrdU+ to total nuclei.
  • TG animals showed 40-60% increase in the number of BrdU+ proliferating cells at all three injection times ( Figure 4C). Therefore, PPAR5 induced increase in the number of quiescent satellite cells yields higher number of fusion competent myoblasts, leading to the enhancement of regenerative capacity of the muscle.
  • PPAR5 activation expedites skeletal muscle regeneration following an acute thermal injury.
  • VP 16- PPAR5 transgenic animals showed increased satellite cell proliferation at the early phase of the regenerative process, which subsequently translated into increased CSA and the number of nascent regenerating fibers.
  • muscle specific over expression of PPAR5 seems to increase the resident satellite cell pool.
  • PPAR5 activation seems to promote rapid emergence of nascent fibers after the injury. There being no evidence of hyperplasia at 21 days after the injury when the regenerative process is essentially complete, it is concluded that the additional nascent fibers efficiently fuse with each other to restore mature fibers (Karpati G, Molnar MJ in Skeletal muscle repair and regeneration, eds Schiaffino S, Partridge T (Springer, Dordrecht), (2008)).
  • PPAR5 activation can bestow infinite abundance of satellite cell population throughout the life of an organism.
  • GW501516 While enhancement in regenerative capacity was observed in both genetic and pharmacological models, the inherent differences in the experimental parameters is acknowledged. Orally administered GW501516 was delivered systemically, presumably activating PPAR5 in a variety of organs and cell types in the animal. However, in VP16- PPAR5 animals, activation of the PPAR5 receptors is limited to the mature muscle fibers. Additionally, genetic background of the animals may affect the efficiency of regeneration after an injury (Grounds and McGeachie, Cell Tissue Res 255(2):385-391 (1989); Roberts et al., J Anat 191:585-594 (1997)). Extramuscular effects of PPAR5 agonist administration may require further investigation when considering clinical use of GW501516 to augment muscle injury treatment. Recently, pharmacological activation of PPAR5 has been shown to improve sarcolemmal integrity in mdx mice (Miura et al., Hum mol Genet 18(23):4640-4649 (2009)
  • PPAR5 not only controls running endurance and metabolic parameters in the muscle, but also its regenerative program.
  • PPAR5 activation affects multiple facets of the regenerative program, exerting comprehensive but transient effects to expedite the progress.
  • PPAR5 may be pharmacologically targeted to enhance the regenerative capacity of the muscle after injury and possibly other degenerative conditions where satellite cell function is compromised.
  • PPAR5 activation can be used to treat other degenerative conditions such as aging induced satellite cell dysfunction and ensuing sarcopenia.
  • CV-1 cells were grown in DMEM+10 charcoal stripped FCS. Cells were seeded into 384-well plates the day before transfection to give a confluency of 50-80% at transfection. A total of 0.8 g DNA containing 0.64 micrograms pCMX-PPARDelta LBD, 0.1 micrograms pCMX.beta.Gal, 0.08 micrograms pGLMH2004 reporter and 0.02 micrograms pCMX empty vector was transfected per well using FuGene transfection reagent according to the manufacturer's instructions (Roche). Cells were allowed to express protein for 48 h followed by addition of compound.
  • Plasmids Human PPAR5 was used to PCR amplify the PPAR5 LBD.
  • the amplified cDNA ligand binding domain (LBD) of PPAR5 isoform was (PPAR5 amino acid 128 to C- terminus) and fused to the DNA binding domain (DBD) of the yeast transcription factor GAL4 by subcloning fragments in frame into the vector pCMX GAL (Sadowski et al. (1992), Gene 118, 137) generating the plasmids pCMX-PPARDelta LBD. Ensuing fusions were verified by sequencing.
  • the pCMXMH2004 lucif erase reporter contains multiple copies of the GAL4 DNA response element under a minimal eukaryotic promoter (Hollenberg and Evans, 1988). pCMXpGal was generated.
  • Luciferase assay Medium including test compound was aspirated and washed with PBS. 50 ⁇ 1 PBS including 1 mM Mg++ and Ca++ were then added to each well. The luciferase assay was performed using the LucLite kit according to the manufacturer's instructions (Packard Instruments). Light emission was quantified by counting on a Perkin Elmer Envision reader. To measure 3-galactosidase activity 25 ⁇ supernatant from each transfection lysate was transferred to a new 384 microplate. Beta-galactosidase assays were performed in the microwell plates using a kit from Promega and read in a Perkin Elmer Envision reader. The beta-galactosidase data were used to normalize (transfection efficiency, cell growth etc.) the lucif erase data.
  • the activity of a compound is calculated as fold induction compared to an untreated sample. For each compound the efficacy (maximal activity) is given as a relative activity compared to GW501516, a PPAR5 agonist.
  • the EC 50 is the concentration giving 50% of maximal observed activity. EC 50 values were calculated via non-linear regression usingGraphPad PRISM (GraphPad Software, San Diego, Calif.).

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Abstract

La présente invention concerne des procédés visant à renforcer l'activité des récepteurs PPARδ et des méthodes de traitement des maladies associées aux récepteurs PPARδ (par exemple les maladies mitochondriales, les maladies musculaires, les maladies vasculaires, les maladies démyélinisantes et les maladies métaboliques).
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WO2017089980A1 (fr) 2015-11-26 2017-06-01 Cadila Healthcare Limited Doubles modulateurs de ppar pour le traitement de la rétinopathie diabétique et des maladies oculaires liées au diabète
ES2643856A1 (es) * 2016-05-24 2017-11-24 Universidad Del Pais Vasco / Euskal Herriko Unibertsitatea Triazoles para la regulación de la homeostasis de calcio intracelular
JP2019533660A (ja) * 2016-10-05 2019-11-21 ミトブリッジ，インコーポレーテッド 急性腎障害を処置する方法
WO2020172421A1 (fr) * 2019-02-20 2020-08-27 Reneo Pharmaceuticals, Inc. Utilisation d'agonistes de ppar-delta dans le traitement de la myopathie mitochondriale
US20230233570A1 (en) * 2022-01-25 2023-07-27 Reneo Pharmaceuticals, Inc. Use of ppar-delta agonists in the treatment of disease

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WO2017044551A1 (fr) * 2015-09-11 2017-03-16 Mitobridge, Inc. Agonistes du récepteur ppar-alpha pour le traitement de maladies mitochondriales
WO2017089980A1 (fr) 2015-11-26 2017-06-01 Cadila Healthcare Limited Doubles modulateurs de ppar pour le traitement de la rétinopathie diabétique et des maladies oculaires liées au diabète
ES2643856A1 (es) * 2016-05-24 2017-11-24 Universidad Del Pais Vasco / Euskal Herriko Unibertsitatea Triazoles para la regulación de la homeostasis de calcio intracelular
US11377427B2 (en) 2016-05-24 2022-07-05 Universidad Del Pais Vasco Triazoles for regulating intracellular calcium homeostasis
JP2019533660A (ja) * 2016-10-05 2019-11-21 ミトブリッジ，インコーポレーテッド 急性腎障害を処置する方法
RU2753607C2 (ru) * 2016-10-05 2021-08-18 Митобридж, Инк. Способы лечения острого повреждения почек
JP7065839B2 (ja) 2016-10-05 2022-05-12 ミトブリッジ，インコーポレーテッド 急性腎障害を処置する方法
WO2020172421A1 (fr) * 2019-02-20 2020-08-27 Reneo Pharmaceuticals, Inc. Utilisation d'agonistes de ppar-delta dans le traitement de la myopathie mitochondriale
CN113710683A (zh) * 2019-02-20 2021-11-26 雷内奥制药公司 PPAR-δ激动剂在治疗线粒体肌病中的用途
US20230233570A1 (en) * 2022-01-25 2023-07-27 Reneo Pharmaceuticals, Inc. Use of ppar-delta agonists in the treatment of disease
US11931365B2 (en) * 2022-01-25 2024-03-19 Reneo Pharmaceuticals, Inc. Use of PPAR-delta agonists in the treatment of disease

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