WO2017044551A1 - Agonistes du récepteur ppar-alpha pour le traitement de maladies mitochondriales - Google Patents

Agonistes du récepteur ppar-alpha pour le traitement de maladies mitochondriales Download PDF

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WO2017044551A1
WO2017044551A1 PCT/US2016/050657 US2016050657W WO2017044551A1 WO 2017044551 A1 WO2017044551 A1 WO 2017044551A1 US 2016050657 W US2016050657 W US 2016050657W WO 2017044551 A1 WO2017044551 A1 WO 2017044551A1
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ppara
effective concentration
half maximal
maximal effective
ppar5
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PCT/US2016/050657
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English (en)
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Ross Fredenburg
Michael Patane
Bharat Lagu
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Mitobridge, Inc.
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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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • 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
    • A61K31/42—Oxazoles
    • A61K31/421—1,3-Oxazoles, e.g. pemoline, trimethadione
    • 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
    • A61K31/42—Oxazoles
    • A61K31/423—Oxazoles condensed with carbocyclic rings
    • 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
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • This application concerns methods of treating mitochondrial diseases, and other related conditions, with PPAR alpha (PPARa) 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 treating mitochondrial diseases.
  • the present invention addresses these and other such needs.
  • PPARa agonists for treating mitochondrial diseases.
  • a method of treating a mitochondrial disease or condition in a subject comprising administering to the subject a therapeutically effective amount of one or more PPARa agonists (see, e.g., Example 1).
  • the methods disclosed herein are useful in modulating the activity of a PPAR protein for the treatment of diseases, developmental delays, and symptoms related to mitochondrial dysfunction.
  • 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
  • PPARa agonists for the preparation of a medicament for the treatment of a mitochondrial disease.
  • PPARa agonist is intended for the treatment of a subject with a mitochondrial disease.
  • PPARa agonists or a pharmaceutical composition comprising one or more PPARa agonists, for use in a method for treating a mitochondrial disease.
  • Figures 2A and 2B are bar graphs showing the dye extraction results from the left tibialis anterior (TA) muscle ( Figure 2A) and the right TA muscle ( Figure 2B).
  • Figures 3A and 3B are graphs (bar graph, Figure 3A; scatter plot, Figure 3B) showing the corrected Evans blue dye optical density for the left TA muscle versus the right TA muscle, wherein the corrected optical density is the left TA muscle dye extraction optical density less the right TA muscle dye extraction optical density.
  • Peroxisome proliferator-activated receptors are members of the nuclear receptor superfamily of ligand-activated transcription factors. Three subtypes of PPARs have been cloned from the mouse and human: i.e. , PPARa, PPARy, and PPAR5. The PPARs are important regulators of carbohydrate and lipid metabolism, cell growth and differentiation, phenotype transition, apoptosis, neovascularization, immunoregulation, and the inflammatory response.
  • PPARa, PPARy, and PPAR5 sequences are publically available, for example from GenBank® sequence database (e.g.
  • PPAR5 (OMIM 600409): accession numbers NP_001165289.1 (human, protein) NP_035275 (mouse, protein), NM_001171818 (human, nucleic acid) and NM_011145 (mouse, nucleic acid)).
  • PPARa agonist refers to substances that selectively increase the activity of PPARa.
  • the term PPARa agonist refers a dual PPARa/ ⁇ agonist, which increases the activity of both PPARa and PPARy.
  • the term PPARa agonist refers a dual PPARa/ ⁇ agonist, which increases the activity of both PPARa and PPAR5.
  • the term PPARa agonist refers a PAN PPARa/ ⁇ / ⁇ agonist, which increases the activity of PPARa, PPARy, and PPAR5.
  • Substances can be tested for their PPARa agonist activity (see, e.g., Xu, Y. et al. J. Med. Chem.2003, 46, 5121-5124) by contacting the substance with cells expressing PPARa, detecting their binding with PPARa and then detecting signals that serve as the indicator of the activation of PPARa.
  • Substances can be tested for their PPARa agonist activity and PPARy agonist activity by first contacting the substance with cells expressing PPARa, detecting their binding with PPARa and then detecting signals that serve as the indicator of the activation of PPARa; and also testing PPARy for by contacting the substance with cells expressing PPARy, detecting their binding with PPARy and then detecting signals that serve as the indicator of the activation of PPARy.
  • Substances can be tested for their PPARa agonist activity and PPAR5 agonist activity by first contacting the substance with cells expressing PPARa, detecting their binding with PPARa and then detecting signals that serve as the indicator of the activation of PPARa; and also testing PPAR5 for 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.
  • Substances can be tested for their PPARa agonist activity, PPARy activity, and PPAR5 agonist activity by first contacting the substance with cells expressing PPARa, detecting their binding with PPARa and then detecting signals that serve as the indicator of the activation of PPARa; also testing PPARy for by contacting the substance with cells expressing PPARy, detecting their binding with PPARy and then detecting signals that serve as the indicator of the activation of PPARy; and also testing PPAR5 for 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.
  • 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.
  • 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, e.g., hydrochloric acid, hydrobromic, phosphoric, nitric, and sulfuric acids) and of organic acids (such as, e.g., acetic acid, benzenesulfonic, benzoic, methanesulfonic, and /?-toluenesulfonic acids).
  • 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 and potassium salts) and alkaline earth metal salts (such as magnesium and calcium salts).
  • 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 coadministered 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).
  • half maximal effective concentration refers to the effective concentration of a therapeutic compound which induces a response halfway between the baseline and maximum after some specified exposure time.
  • 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).
  • “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
  • PPAR agonists also referred to herein as “PPAR agonists” or "PPARa agonists”
  • compounds with PPARa agonist activity including those exhibiting dual PPARa/ ⁇ , dual PPARa/ ⁇ , and/or PAN PPARa/ ⁇ / ⁇ agonist activity, can be used in any of the methods disclosed herein.
  • the compound is a PPARa agonist.
  • the PPARa agonists used in the disclosed methods exhibit a half maximal effective concentration (EC 50 ) for PPARa that is less than 500 nM.
  • the PPARa agonists exhibit a half maximal effective concentration (EC 50 ) for PPARa that is less than 250 nM.
  • the PPARa agonists exhibit a half maximal effective concentration (EC 50 ) for PPARa that is less than 100 nM.
  • the PPARa agonists exhibit a half maximal effective concentration (EC 50 ) for PPARa that is less than 50 nM.
  • the PPARa agonists exhibit a half maximal effective concentration (EC 50 ) for PPARa that is less than 20 nM.
  • the PPARa agonists exhibit a half maximal effective concentration (EC 50) for PPAR5 that is greater than 500 nM.
  • the PPARa agonists exhibit a half maximal effective concentration (EC 50 ) for PPAR5 that is greater than 750 nM.
  • the PPARa agonists exhibit a half maximal effective concentration (EC 50 ) for PPAR5 that is greater than 1000 nM.
  • the PPARa agonists exhibit a half maximal effective concentration (EC 50 ) for PPARa that is less than 500 nM and a half maximal effective concentration (EC 50 ) for PPAR5 that is greater than 500 nM.
  • the PPARa agonists exhibit a half maximal effective concentration (EC 50 ) for PPARa that is less than 250 nM and a half maximal effective concentration (EC 50 ) for
  • the PPARa agonists exhibit a half maximal effective concentration (EC 50 ) for PPARa that is less than 100 nM and a half maximal effective concentration (EC 50 ) for PPAR5 that is greater than 500 nM. In yet other embodiments, the PPARa agonists exhibit a half maximal effective concentration (EC 50 ) for PPARa that is less than 20 nM and a half maximal effective concentration (EC 50) for PPAR5 that is greater than 500 nM.
  • the PPARa agonists exhibit a half maximal effective concentration (EC 50 ) for PPARa that is less than 500 nM and a half maximal effective concentration (EC 50 ) for PPAR5 that is greater than 1000 nM.
  • the PPARa agonists exhibit a half maximal effective concentration (EC 50 ) for PPARa that is less than 250 nM and a half maximal effective concentration (EC 50 ) for
  • the PPARa agonists exhibit a half maximal effective concentration (EC 50 ) for PPARa that is less than 100 nM and a half maximal effective concentration (EC 50 ) for PPAR5 that is greater than 1000 nM. In yet other embodiments, the PPARa agonists exhibit a half maximal effective concentration (EC 50 ) for PPARa that is less than 20 nM and a half maximal effective concentration (EC 50) for PPAR5 that is greater than 1000 nM.
  • the PPARa agonist is selected from the group consisting of:
  • the fibrate is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • the PPARa agonist is selected from the group consisting of:
  • the PPARa agonist is selected from the group consisting of:
  • the PPARa agonist is selected from the group consisting of:
  • the PPARa agonist is selected from the group consisting of:
  • the PPARa agonist is selected from the group consisting of:
  • the PPARa agonist is selected from the group consisting of:
  • the PPARa agonist is selected from the group consisting of:
  • the PPARa agonist is selected from the group consisting of:
  • the PPARa agonist is selected from the group consisting of:
  • the PPARa agonist is selected from the group consisting of:
  • Such methods can include contacting a PPAR protein with an effective amount of a compound or composition provided herein, thereby activating PPAR.
  • the contacting is performed in vitro.
  • the contacting is performed within a subject, such as a human subject, for example by administering a PPARa agonist disclosed herein to the subject.
  • the compound or composition is administered to a healthy subject.
  • the subject is a sedentary or immobilized subject.
  • 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.
  • a healthy subject is also an exercising subject.
  • contacting a PPAR protein in vitro or in vivo with an effective amount of one or more compounds or compositions provided herein increases PPAR 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 PPAR activity in the absence of the compound/composition.
  • Methods of measuring PPAR 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 ah, PLos Biol. 2004, 2, 10, e294 and Lee et al, PNAS 2006, 103, 3444-9).
  • Methods of treating a mitochondrial 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.
  • 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,
  • compositions that include one or more PPARa 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 PPARa agonist can be used in combination with other agents known to have beneficial, additive or synergistic activity with the PPARa agonist.
  • disclosed compounds can be administered alone or in combination with: one or more 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, beza
  • 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, and the particular treatment). 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 mitochondrial disease using the disclosed PPARa agonists for guidance.
  • the precise amount of compound administered to provide an therapeutically effective amount to the subject will depend on the mode of administration, the type, and severity of the cancer, and on the characteristics of the subject, such as general health, age, sex, body weight, and tolerance to drugs. The skilled artisan will be able to determine appropriate dosages depending on these and other factors.
  • an "effective amount" of any additional therapeutic agent(s) will depend on the type of drug used.
  • Suitable dosages are known for approved therapeutic agents and can be adjusted by the skilled artisan according to the condition of the subject, the type of condition(s) being treated and the amount of a compound of the invention being used by following, for example, dosages reported in the literature and recommended in the Physician 's Desk Reference (57th ed., 2003).
  • the disclosed PPARa agonists can be administered to a subject by routes known to one of skill in the art.
  • routes of administration include, but are not limited to, parenteral, e.g., intravenous, intradermal, subcutaneous, oral, intranasal (e.g., inhalation), transdermal, topical, transmucosal, and rectal administration.
  • compositions that include the compound of PPARa 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.
  • composition of the invention is formulated to be compatible with its intended route of administration.
  • the composition is formulated in accordance with routine procedures as a pharmaceutical composition adapted for intravenous, subcutaneous, intramuscular, oral, intranasal, or topical administration to human beings.
  • Example 1 describes in vivo assays for measuring effects of GW501516
  • GW501516 (10 mg/kg) and LY518674 (1 mg/kg and 10 mg/kg) were administered orally once daily for 10 days.
  • the chemical structure of GW501516 and LY518674 are:
  • the sham group and the thermal injury control group were each administered with vehicle (5% ethanol+ 5 % solutol in water) at 10 ml/kg.
  • vehicle 5% ethanol+ 5 % solutol in water
  • freeze injury was done on left tibialis anterior (TA) muscle by placing a 1 gram calibrated weight (Mettler- Toledo) equilibrated to the temperature of dry ice on the belly region of muscle for 10 seconds under Isoflurane/oxygen anesthesia.
  • the incision was closed with 6-o sutures and animals were injected with Buprenorphine (0.1 mg/kg s.c ) during recovery.
  • Figure 1 is a schematic representation the study design.
  • Evans blue dye in injured TA muscles was quantified by incubating TA muscles overnight in 1 mL of sodium sulfate (0.4mL)/acetone (0.6mL) mixture at room temperature. The optical density was measured at 610 nm in duplicate using micro plate reader ( Figures 2A and 2B) and final left TA muscle OD was corrected with the right TA muscle optical density ( Figures 3A and 3B). Plasma and right quadriceps muscle compound levels were measured using LC-MS method. All the data was expressed as mean + SEM and statistical analysis was done using Graph pad prism.
  • Thermal injury group showed significant increase in optical density compared to sham injury animals in Evans blue dye extraction from TA muscle.
  • GW1516 at 10 mg/kg dose showed significant reduction (35%) in optical density compared to thermal injury animals in Evans blue dye extraction from left TA muscle post contralateral OD correction.
  • LY-518674 at 1 mpk & 10 mpk showed 44% and 56% reduction in in optical density compared to thermal injury animals.
  • GW501516 at 10 mg/kg dose showed 8240 + 820 ng/mL plasma levels and 972 + 224 ng/g of tissue levels at 2 hours after the last dose .
  • LY- 518674 at 1 mg/kg and 10 mg/kg showed 965 + 27 ng/mL , 11604 + 663 ng/mL plasma levels and 30 + 3ng/g , 679 + 73 ng/g of muscle levels.

Abstract

La présente invention concerne des procédés pour augmenter l'activité du récepteur PPAR-alpha et des procédés pour le traitement des maladies associées au récepteur PPAR-alpha (par exemple, des maladies mitochondriales).
PCT/US2016/050657 2015-09-11 2016-09-08 Agonistes du récepteur ppar-alpha pour le traitement de maladies mitochondriales WO2017044551A1 (fr)

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US10350184B2 (en) * 2015-04-16 2019-07-16 Metabrain Research Derivatives used in the treatment of muscle atrophy
CN111183129A (zh) * 2017-08-07 2020-05-19 国立大学法人广岛大学 新型邻氨基苯甲酸系化合物、使用了该化合物的Pin1抑制剂、炎症性疾病及癌症的治疗剂
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CN112351975A (zh) * 2018-03-16 2021-02-09 俄克拉何马大学董事会 过氧化物酶体增殖物活化受体α的激动剂和使用方法
US20210386705A1 (en) * 2018-09-25 2021-12-16 Shenzhen Chipscreen Biosciences Co., Ltd. Application of chiglitazar and related compounds thereof
CN111728962A (zh) * 2019-03-25 2020-10-02 泰州华元医药科技有限公司 白藜芦醇衍生物及其抗纤维化的医药用途
CN111728962B (zh) * 2019-03-25 2024-04-30 绍兴君科臻元医药科技有限公司 白藜芦醇衍生物及其抗纤维化的医药用途
US20220185764A1 (en) * 2020-12-10 2022-06-16 Taizhou Huayuan Medicinal Tech Co. Ltd. Resveratrol derivative and anti-fibrotic method using the same

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