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WO2025166338A2 - Inhibition de mpc systémique pour inverser les signes de vieillissement - Google Patents

Inhibition de mpc systémique pour inverser les signes de vieillissement

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Publication number
WO2025166338A2
WO2025166338A2 PCT/US2025/014294 US2025014294W WO2025166338A2 WO 2025166338 A2 WO2025166338 A2 WO 2025166338A2 US 2025014294 W US2025014294 W US 2025014294W WO 2025166338 A2 WO2025166338 A2 WO 2025166338A2
Authority
WO
WIPO (PCT)
Prior art keywords
mpc
inhibitor
systemic administration
mpc inhibitor
nutritional supplement
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/US2025/014294
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English (en)
Inventor
William E. Lowry
Carlos GALVAN
Anthony COVARRUBIAS
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
University of California Berkeley
University of California San Diego UCSD
Original Assignee
University of California Berkeley
University of California San Diego UCSD
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Application filed by University of California Berkeley, University of California San Diego UCSD filed Critical University of California Berkeley
Publication of WO2025166338A2 publication Critical patent/WO2025166338A2/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/57—Nitriles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • HFSCs Hair follicle stem cells
  • telogen telogen- anagen transition
  • Proliferation or activation of HFSCs is well known to be a prerequisite for advancement of the hair cycle.
  • baldness and alopecia continue to be conditions that cannot be successfully treated in all individuals.
  • Some of the existing treatments are inconvenient for users, others require surgical intervention or other invasive procedures.
  • the present disclosure provides a method of: a) systemically inhibiting a mitochondrial pyruvate carrier (MPC) protein; b) inducing adult stem cell activation in an aged tissue; c) reducing at least one sign of aging; d) promoting hair growth; or e) inhibiting age-induced tumorigenesis, comprising systemically administering to a patient an MPC inhibitor.
  • the at least one sign of aging comprises morbidity, slowed, hair cycle, hair graying, ocular occlusion, mobility, kyphosis, cognitive impairment, or any combination thereof.
  • the patient has baldness or alopecia.
  • the adult stem cells are selected from skin cells, muscle cells, adipose cells, liver cells, hair follicle cells, brain cells, blood cells, and any combination thereof.
  • the age-induced tumorigenesis is tumorigenesis in skin, liver, kidney, fat, or a combination thereof.
  • the tumorigenesis in skin is melanoma.
  • the MPC inhibitor may be administered orally, intravenously, or parenterally. In certain preferred embodiments, the MPC inhibitor is administered orally.
  • the present disclosure provides a method of: a) systemically inhibiting a mitochondrial pyruvate carrier (MPC) protein; b) inducing adult stem cell activation in an aged tissue; c) reducing at least one sign of aging; d) promoting hair growth; e) inhibiting age-induced tumorigenesis; f) treating fatty liver disease; or g) treating or slowing muscle wastage, comprising systemically administering to a patient an MPC inhibitor.
  • MPC mitochondrial pyruvate carrier
  • the present disclosure provides a nutritional supplement comprising an MPC inhibitor, wherein the MPC inhibitor is a compound of formula I or II, wherein: each A is independently CH, CR 4 , or N;
  • Y is carboxyl, ester, amide, or ° Z is CH, CR 4 , or N;
  • R 2 is CN or carboxyl
  • R 3 is aralkyl or aralkylacyl, wherein R 3 is substituted by two R 5 in the meta positions, wherein each R 5 is independently selected from alkyl, alkoxy, or halo; each R 4 is independently alkyl, carboxyl, halo, hydroxy, ester, or CN;
  • R 7 is hydrogen, alkyl, halo, hydroxyl, alkoxy, or acyloxy
  • R 10 is hydrogen or alkyl; and n is 0-4; or a pharmaceutically acceptable salt thereof.
  • Figure 1 A summary of phenotypes emerging in aging experiment #2. In this experiment, animals were aged until 2 years of age (late-mid-life for a mouse) and then fed chow with the indicated treatment and have been monitored for up to 4 months.
  • FIGS. 2A-2C Systemic inhibition of pyruvate oxidation by Mpc inhibition improves the frailty index in aged mice.
  • 2A-B Half the mice were fed chow formulated with UK5099 to block pyruvate entry into the mitochondria, and the data show that inhibition of pyruvate oxidation improved the overall appearance of aged mice over the course of 6 months of treatment.
  • 2C in addition, a survival study showed that chronic Mpc inhibition by UK5099 improves animal survival.
  • FIG. 3A Quantification of MPC inhibition on hair growth in aged animals. Two year old mice were shaved and then fed control how or chow made with UK5099. The animals on UK5099 showed an increased rate of hair growth relative to controls. Brackets indicate p-value ⁇ 0.05.
  • Figure 3B shows photographic images of hair growth in mice treated with vehicle and with UK5099.
  • FIG. 4 Animals treated with UK5099 in their chow showed generally decreased rates of liver tumorigenesis. Animals were allowed to age from 24 months to 28 months of age. After dissection, tumor burden was assessed. UK5099 treated animals showed fewer tumors, particularly in liver.
  • FIG. 1 Assay for senescence in peripheral fat.
  • FIG. 7 Genetic deletion of Mpc 1 decreases melanoma grade. Mutations in Braf and Pten were introduced into melanocyte stem cells, causing them to initiate melanoma. In animals also floxed for Mpcl, fewer tumors formed and were less invasive.
  • Figure 8A Genetic or pharmacological deletion of Mpcl decreases proliferation of cells grown in vitro.
  • Cell lines were derived from melanoma generated by either wildtype or Mpcl-KO melanocyte stem cells.
  • FIG. 8B A cell line derived from melanoma created from melanocyte stem cells was treated with control (DMSO) or UK5099, and the growth rate was measured.
  • FIG. 13A Systemic MPC inhibition and effect on hair cycle. Images of mice treated with UK5099.
  • Figure 13B Systemic MPC inhibition and effect on hair cycle. Epidermis thickness of mice treated with UK5099.
  • FIG. 14A Hair growth over time in mice with low, medium, and high doses of UK- 5099.
  • Figure 14B New hair growth over time in mice treated with low, medium, and high doses of UK-5099.
  • Figure 15A Effect of chronic MPC inhibition on adipose tissue. Images of fat tissue in male and female mice treated with UK5099.
  • Figure 15B Effect of chronic MPC inhibition on adipose tissue. Fat cell area of mice treated with low, medium, and high doses of UK5099.
  • Figure 18A The effect of UK5099 on liver SAM cycle in aged mice.
  • Figure 18B The effect of UK5099 on liver histidine metabolism in aged mice.
  • FIG. 20 The effect of UK5099 on liver amino acids in aged mice.
  • the present invention relates to methods to activate aged stem cells with MPC inhibitor compounds that can prevent or reverse aging through manipulation of cellular metabolism. While not being bound by theory, the approach is to pharmacologically and genetically block pyruvate oxidation in aged animals and measure the effects over the course of several months to a year in aged animals. We have advantageously found that that it is possible to administer the MPC inhibitors to mice orally (e.g., via the mouse food, which makes delivery much more efficient). We have now run three separate experiments and found consistent results. While the animals are alive, we quantify visible signs of aging (Frailty Index) and the development of tumors specific to aged animals. In both experiments, all the control mice developed tumors, which makes sense considering that age is the highest risk factor for cancer.
  • mice treated with UK5099 developed tumors, and the tumor burden was reduced on a per animal basis. Additionally, Mice treated with UK5099 have a more robust hair cycle, improved fat deposition, and diminished muscle wasting. Therefore, we now know that systemic Mpc inhibition can activate at least some adult stem cells, promote regeneration and inhibit tumorigenesis.
  • Aging is known to be the strongest risk factor for cancer. Indeed, every control aged animal we have harvested showed evidence of some type of cancer. On the other hand, the rate of tumorigenesis in aged animals treated with an inhibitor of pyruvate oxidation was significantly lower.
  • the present methods may advantageously promote regeneration and prevent tumorigenesis during aging.
  • the present disclosure provides a method of: a) systemically inhibiting a mitochondrial pyruvate carrier (MPC) protein; b) inducing adult stem cell activation in an aged tissue; c) reducing at least one sign of aging; d) promoting hair growth; or e) inhibiting age-induced tumorigenesis, comprising systemically administering to a patient an MPC inhibitor.
  • MPC mitochondrial pyruvate carrier
  • the at least one sign of aging comprises morbidity, slowed, hair cycle, hair graying, ocular occlusion, mobility, kyphosis, cognitive impairment, or any combination thereof.
  • FI Frailty Index
  • Signs of aging may be evaluated, in some embodiments, with a Frailty Index (FI).
  • FI is defined as the proportion of deficits present in an individual out of the total number of age- related health variables considered.
  • a frailty index can be created in most secondary data sources related to health by utilizing health deficits that are routinely collected in health assessments. These deficits include diseases, signs and symptoms, laboratory abnormalities, cognitive impairments, and disabilities in activities of daily living.
  • Frailty Index (number of health deficits present) (number of health deficits measured)
  • the patient has baldness or alopecia.
  • the adult stem cells are selected from skin cells, muscle cells, adipose cells, liver cells, hair follicle cells, brain cells, blood cells, and any combination thereof.
  • the age-induced tumorigenesis is tumorigenesis in skin, liver, kidney, fat, or a combination thereof.
  • the tumorigenesis in skin is melanoma.
  • Exemplary compounds useful for systemic inhibition of MPC according to the present methods, along with their syntheses, are described in U.S. Patent No. 11,312,714, and Published Applications: US 2022/0048908 Al, US 2024/0327400 Al, US 2023/0322765 Al, each of which is hereby incorporated by reference in its entirety.
  • the present disclosure provides a method of: a) systemically inhibiting a mitochondrial pyruvate carrier (MPC) protein; b) inducing adult stem cell activation in an aged tissue; c) reducing at least one sign of aging; d) promoting hair growth; e) inhibiting age-induced tumorigenesis; f) treating fatty liver disease; or g) treating or slowing muscle wastage, comprising systemically administering to a patient an MPC inhibitor.
  • MPC mitochondrial pyruvate carrier
  • the method comprises: a) systemically inhibiting a mitochondrial pyruvate carrier (MPC) protein; b) inducing adult stem cell activation in an aged tissue; c) reducing at least one sign of aging; d) promoting hair growth; or e) inhibiting age-induced tumorigenesis, comprising systemically administering to a patient an MPC inhibitor.
  • the method comprises systemically inhibiting a mitochondrial pyruvate carrier (MPC) protein.
  • the method comprises inducing adult stem cell activation in an aged tissue.
  • the method comprises reducing at least one sign of aging.
  • the method comprises promoting hair growth.
  • the method comprises inhibiting age-induced tumorigenesis.
  • the method comprises treating fatty liver disease.
  • the method comprises treating or slowing muscle wastage.
  • the MPC inhibitor is a compound of formula I or II, wherein: each A is independently CH, CR 4 , or N;
  • Y is carboxyl, ester, amide, or ° ;
  • Z is CH, CR 4 , or N.
  • R 2 is CN or carboxyl
  • R 3 is H, aryl, aralkyl, or aralkylacyl, and is optionally substituted by one or more R 5 , wherein each R 5 is independently selected from alkyl, alkoxy, or halo; each instance of R 4 is independently alkyl, carboxyl, halo, hydroxy, ester, or CN;
  • R 7 is hydrogen, alkyl, halo, hydroxyl, alkoxy, or acyloxy
  • R 10 is hydrogen or alkyl; and n is 0-4; or a pharmaceutically acceptable salt thereof.
  • Z is CH or N.
  • the compound is a compound of formula III, wherein,
  • Y is carboxyl, ester, amide, or O ;
  • R 2 is CN or carboxyl
  • R 3 is H, aryl, aralkyl, or aralkylacyl, and is optionally substituted by one or more R 5 , wherein each R 5 is independently selected from alkyl, alkoxy, or halo; each instance of R 4 is independently alkyl, carboxyl, halo, hydroxy, ester, or CN;
  • R 6 is from H, alkyl, or cycloalkyl
  • R 7 is hydrogen, alkyl, halo, hydroxyl, alkoxy, or acyloxy
  • R 10 is hydrogen or alkyl
  • R 11 is H or alkyl; and n is 0-4; or a pharmaceutically acceptable salt thereof.
  • Y is ° .
  • R 10 is H.
  • R 10 is alkyl (e.g ethyl).
  • Y is ester or amide.
  • R 11 is alkyl (e.g., methyl).
  • the MPC inhibitor is a compound of formula V, VI, or VII, wherein: each A is independently CH, CR 4 , or N;
  • X is NR 6 or O;
  • R 1 is H or lower alkyl; or either R 1 and R 6 or R 1 and R 2 , together with the atoms that separate them, complete a heterocycle;
  • R 2 is CN or carboxyl
  • R 3 is H, aryl, aralkyl, or aralkylacyl, and is optionally substituted by one or more R 5 , wherein each R 5 is independently selected from alkyl, alkoxy, or halo; each instance of R 4 is independently alkyl, carboxyl, halo, hydroxy, or CN;
  • R 6 is from H, alkyl, or cycloalkyl
  • R 7 is hydrogen, alkyl, halo, hydroxyl, alkoxy, or acyloxy; and n is 0-4; or a pharmaceutically acceptable salt thereof.
  • At least one A is N. In certain embodiments, exactly one A is
  • the MPC inhibitor is a compound of formula Va, Via, or
  • X is NR 6 or O
  • R 1 is H or lower alkyl
  • R 2 is CN or carboxyl; or R 1 and R 2 , together with the atoms that separate them, complete a heterocycle;
  • R 3 is H, phenyl, or benzyl, and is optionally substituted by one or more R 5 , wherein each R 5 is independently selected from alkyl, alkoxy, or halo; each instance of R 4 is independently selected from alkyl, carboxyl, halo, hydroxy, or CN;
  • R 6 is selected from H, alkyl, or cycloalkyl; and n is 0-4; or a pharmaceutically acceptable salt thereof.
  • X is NH. In certain embodiments, X is O.
  • R 1 is H. In certain embodiments, R 1 is lower alkyl.
  • R 1 and R 6 together with the atoms that separate them, complete a heterocycle (e.g., morpholinyl).
  • R 6 is hydrogen.
  • R 2 is CN.
  • R 2 is carboxyl.
  • R 1 and R 2 together with the atoms that separate them, complete a heterocyclyl selected from thiazolidine-2,4-dion-5-ylidene or 2-iminothiazolidin- 4-one-5-ylidene.
  • the MPC inhibitor is a compound of formula Va.
  • the MPC inhibitor is a compound of formula Via.
  • R 3 is H. In certain embodiments, R 3 is phenyl. In certain embodiments, R 3 is phenyl and is substituted by one or more R 5 . In certain embodiments, R 3 is substituted by one R 5 , and wherein R 5 is an alkoxy. In certain embodiments, R 3 is aralkyl (e.g., benzyl or phenethyl). In certain embodiments, R 3 is aralkyl. In certain embodiments, R 3 is aralkylacyl (e.g., phenylacetyl). In certain embodiments, R 3 is benzyl. In certain embodiments, R 3 is benzyl and is substituted by one or more R 5 .
  • R 3 is aralkyl (e.g., benzyl or phenethyl). In certain embodiments, R 3 is aralkyl. In certain embodiments, R 3 is aralkylacyl (e.g., phenylacetyl). In certain embodiment
  • R 3 is aralkyl (e.g., benzyl or phenethyl) and is substituted by one or more R 5 (preferably on the phenyl ring).
  • R 3 is aralkylacyl (e.g., phenylacetyl), and is substituted by one or more R 5 (preferably on the phenyl ring).
  • R 3 is substituted by one or two R 5 , wherein each R 5 is independently selected from fluoroalkyl or fluoro.
  • R 3 is substituted by two R 5 , and wherein each R 5 is independently selected from fluoroalkyl or fluoro.
  • R 3 is substituted by two R 5 , wherein each R 5 is trifluoromethyl.
  • R 3 is substituted by two R 5 in the meta positions, wherein each R 5 is trifluoromethyl.
  • the MPC inhibitor is a compound of formula Vb: certain embodiments, n is 0.
  • the MPC inhibitor is a compound of formula Vc: certain embodiments, n is 1.
  • the MPC inhibitor is a compound of formula Vd:
  • R 4 is selected from halo or haloalkyl. In certain embodiments, R 4 is halo (e.g., chloro or bromo).
  • the compound is of formula VI.
  • the compound is of formula Via.
  • n 0.
  • n is 2, and R 4 is selected from halo or haloalkyl.
  • the compound is of formula VII.
  • the compound is of formula Vila.
  • R 7 is hydrogen, hydroxyl, halo (e.g., chloro), or acyloxy (e.g., acetyloxy). In certain embodiments, R 7 is hydroxyl, halo (e.g., chloro), or acyloxy (e.g., acetyloxy).
  • the MPC inhibitor is selected from:
  • the MPC inhibitor is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein:
  • Y is carboxyl, ester, amide
  • R 1 is H, aryl, aralkyl, or aralkylacyl, and is optionally substituted by one or more R 5 ;
  • R 2 is CN or carboxyl
  • R 4 is independently alkyl, alkenyl, alkynyl, azido, halo, hydroxy, carboxyl, ester, or CN;
  • R 5 is independently selected from alkyl, alkoxy, or halo; and n is 0-4.
  • R 10 is H. In certain embodiments, R 10 is alkyl (e.g., ethyl).
  • Y is ester or carboxyl.
  • R 2 is CN. In certain embodiments, R 2 is carboxyl.
  • R 1 is H. In certain embodiments, R 1 is aralkyl (e.g., benzyl or phenethyl). In certain embodiments, R 1 is aralkyl (e.g., benzyl or phenethyl) and is substituted by one or more R 5 (preferably on the phenyl ring). In certain embodiments, R 1 is aralkylacyl (e.g., phenylacetyl), and is substituted by one or more R 5 (preferably on the phenyl ring). In certain embodiments, R 1 is substituted by one or two R 5 , and wherein each R 5 is independently selected from fluoroalkyl or fluoro. In certain embodiments, R 1 is substituted by two R 5 , and wherein each R 5 is trifluoromethyl.
  • R 4 is selected from iodo, fluoro, alkenyl (e.g., vinyl), CN, azido, alkynyl (e.g., acetylenyl), fluoroalkyl (e.g., trifluoromethyl), carboxyl, and ester (e.g., methyl ester or ethyl ester). In certain embodiments, R 4 is not chloro or bromo.
  • the MPC inhibitor is a compound of formula la: wherein R 6 is H, alkyl, aryl, or aralkyl.
  • the MPC inhibitor is selected from: pharmaceutically acceptable salt thereof.
  • the at least one sign of aging comprises morbidity, slowed hair cycle, hair graying, ocular occlusion, mobility, kyphosis, cognitive impairment, or any combination thereof.
  • the patient has baldness or alopecia.
  • the adult stem cells are selected from skin cells, muscle cells, adipose cells, liver cells, hair follicle cells, brain cells, blood cells, and any combination thereof.
  • the age-induced tumorigenesis is tumorigenesis in skin, liver, kidney, fat, or a combination thereof.
  • the tumorigenesis in skin is melanoma.
  • the MPC inhibitor is administered orally. In certain embodiments, the MPC inhibitor is administered intravenously. In certain embodiments, the MPC inhibitor is administered parenterally.
  • the MPC inhibitor is administered for at least about a week. In certain embodiments, the MPC inhibitor is administered for at least about a month. In certain embodiments, the MPC inhibitor is administered for at least about two months. In certain embodiments, the MPC inhibitor is administered for at least about six months. In certain embodiments, the MPC inhibitor is administered for at least about a year. In certain embodiments, the MPC inhibitor is administered for at least about two years.
  • the MPC inhibitor is administered daily.
  • the patient has a ratio of muscle tissue to fat tissue, and wherein said ratio of muscle tissue to fat tissue remains the same following the systemic administration of the MPC inhibitor relative to the ratio prior to the systemic administration of the MPC inhibitor. In certain embodiments, the patient has a ratio of muscle tissue to fat tissue, and wherein said ratio of muscle tissue to fat tissue increases following the systemic administration of the MPC inhibitor relative to the ratio prior to the systemic administration of the MPC inhibitor. In certain embodiments, following the systemic administration of the MPC inhibitor for at least about a week, the ratio of muscle tissue to fat tissue increases by at least about 5% relative to the ratio prior to the systemic administration of the MPC inhibitor.
  • the ratio of muscle tissue to fat tissue increases by at least about 5% relative to the ratio prior to the systemic administration of the MPC inhibitor. In certain embodiments, following the systemic administration of the MPC inhibitor for at least about a month, the ratio of muscle tissue to fat tissue increases by at least about 5% relative to the ratio prior to the systemic administration of the MPC inhibitor. In certain embodiments, following the systemic administration of the MPC inhibitor for at least about two months, the ratio of muscle tissue to fat tissue increases by at least about 5% relative to the ratio prior to the systemic administration of the MPC inhibitor.
  • the ratio of muscle tissue to fat tissue increases by at least about 5% relative to the ratio prior to the systemic administration of the MPC inhibitor. In certain embodiments, following the systemic administration of the MPC inhibitor for at least about a year, the ratio of muscle tissue to fat tissue increases by at least about 5% relative to the ratio prior to the systemic administration of the MPC inhibitor. In certain embodiments, following the systemic administration of the MPC inhibitor for at least about two years, the ratio of muscle tissue to fat tissue increases by at least about 5% relative to the ratio prior to the systemic administration of the MPC inhibitor.
  • the ratio of muscle tissue to fat tissue increases by at least about 10% relative to the ratio prior to the systemic administration of the MPC inhibitor. In certain embodiments, following the systemic administration of the MPC inhibitor for at least about two weeks, the ratio of muscle tissue to fat tissue increases by at least about 10% relative to the ratio prior to the systemic administration of the MPC inhibitor. In certain embodiments, following the systemic administration of the MPC inhibitor for at least about a month, the ratio of muscle tissue to fat tissue increases by at least about 10% relative to the ratio prior to the systemic administration of the MPC inhibitor.
  • the ratio of muscle tissue to fat tissue increases by at least about 10% relative to the ratio prior to the systemic administration of the MPC inhibitor. In certain embodiments, following the systemic administration of the MPC inhibitor for at least about six months, the ratio of muscle tissue to fat tissue increases by at least about 10% relative to the ratio prior to the systemic administration of the MPC inhibitor. In certain embodiments, following the systemic administration of the MPC inhibitor for at least about a year, the ratio of muscle tissue to fat tissue increases by at least about 10% relative to the ratio prior to the systemic administration of the MPC inhibitor. In certain embodiments, following the systemic administration of the MPC inhibitor for at least about two years, the ratio of muscle tissue to fat tissue increases by at least about 10% relative to the ratio prior to the systemic administration of the MPC inhibitor.
  • the ratio of muscle tissue to fat tissue increases by at least about 50% relative to the ratio prior to the systemic administration of the MPC inhibitor. In certain embodiments, following the systemic administration of the MPC inhibitor for at least about two weeks, the ratio of muscle tissue to fat tissue increases by at least about 50% relative to the ratio prior to the systemic administration of the MPC inhibitor. In certain embodiments, following the systemic administration of the MPC inhibitor for at least about a month, the ratio of muscle tissue to fat tissue increases by at least about 50% relative to the ratio prior to the systemic administration of the MPC inhibitor.
  • the ratio of muscle tissue to fat tissue increases by at least about 50% relative to the ratio prior to the systemic administration of the MPC inhibitor. In certain embodiments, following the systemic administration of the MPC inhibitor for at least about six months, the ratio of muscle tissue to fat tissue increases by at least about 50% relative to the ratio prior to the systemic administration of the MPC inhibitor. In certain embodiments, following the systemic administration of the MPC inhibitor for at least about a year, the ratio of muscle tissue to fat tissue increases by at least about 50% relative to the ratio prior to the systemic administration of the MPC inhibitor. In certain embodiments, following the systemic administration of the MPC inhibitor for at least about two years, the ratio of muscle tissue to fat tissue increases by at least about 50% relative to the ratio prior to the systemic administration of the MPC inhibitor.
  • the ratio of muscle tissue to fat tissue increases by at least about 100% relative to the ratio prior to the systemic administration of the MPC inhibitor. In certain embodiments, following the systemic administration of the MPC inhibitor for at least about two weeks, the ratio of muscle tissue to fat tissue increases by at least about 100% relative to the ratio prior to the systemic administration of the MPC inhibitor. In certain embodiments, following the systemic administration of the MPC inhibitor for at least about a month, the ratio of muscle tissue to fat tissue increases by at least about 100% relative to the ratio prior to the systemic administration of the MPC inhibitor.
  • the ratio of muscle tissue to fat tissue increases by at least about 100% relative to the ratio prior to the systemic administration of the MPC inhibitor. In certain embodiments, following the systemic administration of the MPC inhibitor for at least about six months, the ratio of muscle tissue to fat tissue increases by at least about 100% relative to the ratio prior to the systemic administration of the MPC inhibitor. In certain embodiments, following the systemic administration of the MPC inhibitor for at least about a year, the ratio of muscle tissue to fat tissue increases by at least about 100% relative to the ratio prior to the systemic administration of the MPC inhibitor. In certain embodiments, following the systemic administration of the MPC inhibitor for at least about two years, the ratio of muscle tissue to fat tissue increases by at least about 100% relative to the ratio prior to the systemic administration of the MPC inhibitor.
  • the MPC inhibitor following systemic administration of the MPC inhibitor, is essentially not detectable in skin. In certain embodiments, following systemic administration of the MPC inhibitor, the MPC inhibitor is not detectable in skin. In certain embodiments, the MPC inhibitor is detected via mass spectrometry. In certain embodiments, the MPC detection method is liquid chromatography -mass spectrometry.
  • the present disclosure provides a nutritional supplement comprising an MPC inhibitor, wherein the MPC inhibitor is a compound of formula I or II, wherein: each A is independently CH, CR 4 , or N;
  • Y is carboxyl, ester, amide, or °
  • Z is CH, CR 4 , or N.
  • R 2 is CN or carboxyl;
  • R 3 is aralkyl or aralkylacyl, wherein R 3 is substituted by two R 5 in the meta positions, wherein each R 5 is independently selected from alkyl, alkoxy, or halo; each R 4 is independently alkyl, carboxyl, halo, hydroxy, ester, or CN;
  • R 7 is hydrogen, alkyl, halo, hydroxyl, alkoxy, or acyloxy
  • R 10 is hydrogen or alkyl; and n is 0-4; or a pharmaceutically acceptable salt thereof.
  • Z is CH or N.
  • the MPC inhibitor is a compound of formula III, wherein,
  • Y is carboxyl, ester, amide, or ° ;
  • R 2 is CN or carboxyl
  • R 3 is aralkyl or aralkylacyl, wherein R 3 is substituted by two R 5 in the meta positions, wherein each R 5 is independently selected from alkyl, alkoxy, or halo; each R 4 is independently alkyl, carboxyl, halo, hydroxy, ester, or CN;
  • R 7 is hydrogen, alkyl, halo, hydroxyl, alkoxy, or acyloxy
  • R 10 is hydrogen or alkyl; or a pharmaceutically acceptable salt thereof.
  • Y is O .
  • R 10 is H.
  • R 10 is alkyl (e.g., ethyl).
  • Y is ester or amide.
  • the MPC inhibitor is a compound of formula V, VI, or VII, wherein: each A is independently CH, CR 4 , or N;
  • X is NR 6 or O
  • R 1 is H or lower alkyl; or either R 1 and R 6 or R 1 and R 2 , together with the atoms that separate them, complete a heterocycle;
  • R 2 is CN or carboxyl
  • R 3 is aralkyl or aralkylacyl, wherein R 3 is substituted by two R 5 in the meta positions, wherein each R 5 is independently selected from alkyl, alkoxy, or halo; each R 4 is independently alkyl, carboxyl, halo, hydroxy, or CN;
  • R 6 is from H, alkyl, or cycloalkyl
  • R 7 is hydrogen, alkyl, halo, hydroxyl, alkoxy, or acyloxy; and n is 0-4; or a pharmaceutically acceptable salt thereof.
  • At least one A is N. In certain embodiments, exactly one A is
  • the MPC inhibitor is a compound of formula Va, Via, or
  • X is NR 6 or O
  • R 1 is H or lower alkyl
  • R 2 is CN or carboxyl; or R 1 and R 2 , together with the atoms that separate them, complete a heterocycle;
  • R 3 is benzyl, wherein R 3 is substituted by two R 5 in the meta positions, wherein each R 5 is independently selected from alkyl, alkoxy, or halo; each R 4 is independently selected from alkyl, carboxyl, halo, hydroxy, or CN;
  • R 6 is selected from H, alkyl, or cycloalkyl; and n is 0-4; or a pharmaceutically acceptable salt thereof.
  • X is NH
  • X is O. In certain embodiments, R 1 is H.
  • R 1 is lower alkyl. In certain embodiments, R 1 and R 6 , together with the atoms that separate them, complete a heterocycle (e.g., morpholinyl). In certain embodiments, R 6 is hydrogen.
  • R 2 is CN. In certain embodiments, R 2 is carboxyl. In certain embodiments, R 1 and R 2 , together with the atoms that separate them, complete a heterocyclyl selected from thiazolidine-2,4-dion-5-ylidene or 2-iminothiazolidin-4-one-5-ylidene.
  • the compound is of formula Va.
  • the compound is of formula Via.
  • R 3 is aralkyl (e.g., benzyl or phenethyl). In certain embodiments, R 3 is aralkylacyl (e.g., phenylacetyl). In certain embodiments, R 3 is benzyl.
  • each R 5 is independently selected from fluoroalkyl or fluoro. In certain embodiments, each R 5 is trifluoromethyl.
  • the MPC inhibitor is a compound of formula Vb:
  • n is 0. In certain embodiments, n is 1.
  • the MPC inhibitor is a compound of formula Vd:
  • the MPC inhibitor is a compound of formula Ve:
  • R 4 is selected from halo or haloalkyl. In certain embodiments, R 4 is halo (e.g., chloro or bromo).
  • the MPC inhibitor is a compound of formula VI.
  • the MPC inhibitor is a compound of formula Via.
  • n is 0. In certain embodiments, n is 2, and R 4 is selected from halo or haloalkyl.
  • the MPC inhibitor is a compound of formula VII.
  • the MPC inhibitor is a compound of formula Vila.
  • R 7 is hydrogen, hydroxyl, halo (e.g., chloro), or acyloxy (e.g., acetyloxy). In certain embodiments, R 7 is hydroxyl, halo (e.g., chloro), or acyloxy (e.g., acetyloxy).
  • the MPC inhibitor is selected from:
  • the MPC inhibitor is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein: OR 10
  • Y is carboxyl, ester, amide, or 0 ;
  • R 1 is aralkyl or aralkylacyl, wherein R 3 is substituted by two R 5 in the meta positions;
  • R 2 is CN or carboxyl; independently alkyl, alkenyl, alkynyl, azido, halo, hydroxy, carboxyl, ester, or CN; and is independently selected from alkyl, alkoxy, or halo.
  • Y is 0 .
  • R 10 is H.
  • R 10 is alkyl (e.g., ethyl).
  • Y is ester or carboxyl.
  • R 2 is CN. In certain embodiments, R 2 is carboxyl.
  • R 1 is aralkyl (e.g., benzyl or phenethyl). In certain embodiments, R 1 is aralkylacyl (e.g., phenylacetyl).
  • each R 5 is independently selected from fluoroalkyl or fluoro. In certain embodiments, each R 5 is trifluoromethyl.
  • R 4 is selected from iodo, fluoro, alkenyl (e.g., vinyl), CN, azido, alkynyl (e.g., acetylenyl), fluoroalkyl (e.g., trifluoromethyl), carboxyl, and ester (e.g., methyl ester or ethyl ester). In certain embodiments, R 4 is not chloro or bromo.
  • the MPC inhibitor is a compound of formula la: wherein R 6 is H, alkyl, aryl, or aralkyl,
  • the MPC inhibitor is selected from:
  • the nutritional supplement further comprises a multivitamin complex.
  • the compounds described herein may be administered systemically as a pharmaceutical composition.
  • the individual is a mammal such as a human, or a non-human mammal.
  • the composition or the compound is preferably administered as a pharmaceutical composition comprising, for example, a compound of the invention and a pharmaceutically acceptable carrier.
  • Pharmaceutically acceptable carriers include, for example, aqueous solutions such as water or physiologically buffered saline or other solvents or vehicles such as glycols, glycerol, oils such as olive oil, or injectable organic esters.
  • the aqueous solution is pyrogen-free, or substantially pyrogen-free.
  • the excipients can be chosen, for example, to effect delayed release of an agent or to selectively target one or more cells, tissues or organs.
  • the pharmaceutical composition can be in dosage unit form such as tablet, capsule (including sprinkle capsule and gelatin capsule), granule, lyophile for reconstitution, powder, solution, syrup, suppository, injection or the like.
  • the composition can also be present in a transdermal delivery system, e.g., a skin patch.
  • a pharmaceutically acceptable carrier can contain physiologically acceptable agents that act, for example, to stabilize, increase solubility or to increase the absorption of a compound such as a compound of the invention.
  • physiologically acceptable agents include, for example, carbohydrates, such as glucose, sucrose or dextrans, antioxidants, such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins or other stabilizers or excipients.
  • the choice of a pharmaceutically acceptable carrier, including a physiologically acceptable agent depends, for example, on the route of administration of the composition.
  • the preparation or pharmaceutical composition can be a self-emulsifying drug delivery system or a self-microemulsifying drug delivery system.
  • the pharmaceutical composition also can be a liposome or other polymer matrix, which can have incorporated therein, for example, a compound of the invention.
  • Liposomes for example, which comprise phospholipids or other lipids, are nontoxic, physiologically acceptable and metabolizable carriers that are relatively simple to make and administer.
  • phrases "pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable carrier means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material useful for formulating a drug for medicinal or therapeutic use.
  • a pharmaceutically acceptable material, composition or vehicle such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material useful for formulating a drug for medicinal or therapeutic use.
  • Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
  • materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as com starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, com oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydrox
  • a pharmaceutical composition can be administered to a subject by any of a number of routes of administration including, for example, orally (for example, drenches as in aqueous or non-aqueous solutions or suspensions, tablets, capsules (including sprinkle capsules and gelatin capsules), boluses, powders, granules, pastes for application to the tongue); absorption through the oral mucosa (e.g., sublingually); subcutaneously; trans- dermally (for example as a patch applied to the skin); and topically (for example, as a cream, ointment or spray applied to the skin).
  • the compound may also be formulated for inhalation.
  • a compound may be simply dissolved or suspended in sterile water.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy.
  • the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration.
  • the amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 1 percent to about ninety-nine percent of active ingredient, preferably from about 5 percent to about 70 percent, most preferably from about 10 percent to about 30 percent.
  • Methods of preparing these formulations or compositions include the step of bringing into association an active compound, such as a compound of the invention, with the carrier and, optionally, one or more accessory ingredients.
  • an active compound such as a compound of the invention
  • the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.
  • Formulations of the invention suitable for oral administration may be in the form of capsules (including sprinkle capsules and gelatin capsules), cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), lyophile, powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in- water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient.
  • Compositions or compounds may also be administered as a bolus, electuary or paste.
  • the active ingredient is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents,
  • pharmaceutically acceptable carriers such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose
  • compositions may also comprise buffering agents.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets, and other solid dosage forms of the pharmaceutical compositions may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres.
  • compositions may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved in sterile water, or some other sterile injectable medium immediately before use.
  • These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner.
  • embedding compositions that can be used include polymeric substances and waxes.
  • the active ingredient can also be in micro- encapsulated form, if appropriate, with one or more of the above-described excipients.
  • Liquid dosage forms useful for oral administration include pharmaceutically acceptable emulsions, lyophiles for reconstitution, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, cyclodextrins and derivatives thereof, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art, such
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
  • Suspensions in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • Powders and sprays can contain, in addition to an active compound, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
  • Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.
  • Transdermal patches have the added advantage of providing controlled delivery of a compound of the present invention to the body.
  • dosage forms can be made by dissolving or dispersing the active compound in the proper medium.
  • Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel.
  • parenteral administration and “administered parenterally” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrastemal injection and infusion.
  • compositions suitable for parenteral administration comprise one or more active compounds in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.
  • aqueous and nonaqueous carriers examples include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate.
  • polyols such as glycerol, propylene glycol, polyethylene glycol, and the like
  • vegetable oils such as olive oil
  • injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents that delay absorption such as aluminum monostearate and gelatin.
  • the absorption of the drug in order to prolong the effect of a drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution, which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.
  • Injectable depot forms are made by forming microencapsulated matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissue.
  • active compounds can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of active ingredient in combination with a pharmaceutically acceptable carrier.
  • Methods of introduction may also be provided by rechargeable or biodegradable devices.
  • Various slow release polymeric devices have been developed and tested in vivo in recent years for the controlled delivery of drugs, including proteinaceous biopharmaceuticals.
  • a variety of biocompatible polymers including hydrogels, including both biodegradable and non-degradable polymers, can be used to form an implant for the sustained release of a compound at a particular target site.
  • Actual dosage levels of the active ingredients in the pharmaceutical compositions may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
  • the selected dosage level will depend upon a variety of factors including the activity of the particular compound or combination of compounds employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion of the particular compound(s) being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound(s) employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.
  • a physician or veterinarian having ordinary skill in the art can readily determine and prescribe the therapeutically effective amount of the pharmaceutical composition required.
  • the physician or veterinarian could start doses of the pharmaceutical composition or compound at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.
  • therapeutically effective amount is meant the amount of a compound that is sufficient to elicit the desired therapeutic effect. It is generally understood that the effective amount of the compound will vary according to the weight, sex, age, and medical history of the subject. Other factors which influence the effective amount may include, but are not limited to, the severity of the patient's condition, the disorder being treated, the stability of the compound, and, if desired, another type of therapeutic agent being administered with the compound of the invention.
  • a larger total dose can be delivered by multiple administrations of the agent.
  • Methods to determine efficacy and dosage are known to those skilled in the art (Isselbacher et al. (1996) Harrison’s Principles of Internal Medicine 13 ed., 1814-1882, herein incorporated by reference).
  • a suitable daily dose of an active compound used in the compositions and methods of the invention will be that amount of the compound that is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above.
  • the effective daily dose of the active compound may be administered as one, two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms.
  • the active compound may be administered two or three times daily. In preferred embodiments, the active compound will be administered once daily.
  • the patient receiving this treatment is any animal in need, including primates, in particular humans; and other mammals such as equines, cattle, swine, sheep, cats, and dogs; poultry; and pets in general.
  • compounds of the invention may be used alone or conjointly administered with another type of therapeutic agent.
  • contemplated salts of the invention include, but are not limited to, alkyl, dialkyl, trialkyl or tetra-alkyl ammonium salts.
  • contemplated salts of the invention include, but are not limited to, L-arginine, benenthamine, benzathine, betaine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2- (diethylamino)ethanol, ethanolamine, ethylenediamine, N-methylglucamine, hydrabamine, IH-imidazole, lithium, L-lysine, magnesium, 4-(2-hydroxyethyl)morpholine, piperazine, potassium, l-(2-hydroxyethyl)pyrrolidine, sodium, triethanolamine, tromethamine, and zinc salts.
  • contemplated salts of the invention include, but are not limited to, Na, Ca, K, Mg, Zn or other metal salts.
  • contemplated salts of the invention include, but are not limited to, l-hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, 1-ascorbic acid, 1-aspartic acid, benzenesulfonic acid, benzoic acid, (+)-camphoric acid, (+)-camphor-10-sulfonic acid, capric acid (decanoic acid), caproic acid (hexanoic acid), caprylic acid (octanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethan
  • the pharmaceutically acceptable acid addition salts can also exist as various solvates, such as with water, methanol, ethanol, dimethylformamide, and the like. Mixtures of such solvates can also be prepared.
  • the source of such solvate can be from the solvent of crystallization, inherent in the solvent of preparation or crystallization, or adventitious to such solvent.
  • wetting agents such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.
  • antioxidants examples include: (1) water-soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal-chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.
  • water-soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like
  • oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), le
  • agent is used herein to denote a chemical compound (such as an organic or inorganic compound, a mixture of chemical compounds), a biological macromolecule (such as a nucleic acid, an antibody, including parts thereof as well as humanized, chimeric and human antibodies and monoclonal antibodies, a protein or portion thereof, e.g., a peptide, a lipid, a carbohydrate), or an extract made from biological materials such as bacteria, plants, fungi, or animal (particularly mammalian) cells or tissues.
  • Agents include, for example, agents whose structure is known, and those whose structure is not known. The ability of such agents to inhibit AR or promote AR degradation may render them suitable as “therapeutic agents” in the methods and compositions of this disclosure.
  • a “patient,” “subject,” or “individual” are used interchangeably and refer to either a human or a non-human animal. These terms include mammals, such as humans, primates, livestock animals (including bovines, porcines, etc.), companion animals (e.g., canines, felines, etc.) and rodents (e.g., mice and rats).
  • Treating” a condition or patient refers to taking steps to obtain beneficial or desired results, including clinical results.
  • treatment is an approach for obtaining beneficial or desired results, including clinical results.
  • Beneficial or desired clinical results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, diminishment of extent of disease, stabilized (i.e. not worsening) state of disease, preventing spread of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable.
  • Treatment can also mean prolonging survival as compared to expected survival if not receiving treatment.
  • preventing is art-recognized, and when used in relation to a condition, such as a local recurrence (e.g., pain), a disease such as cancer, a syndrome complex such as heart failure or any other medical condition, is well understood in the art, and includes administration of a composition which reduces the frequency of, or delays the onset of, symptoms of a medical condition in a subject relative to a subject which does not receive the composition.
  • a condition such as a local recurrence (e.g., pain)
  • a disease such as cancer
  • a syndrome complex such as heart failure or any other medical condition
  • prevention of cancer includes, for example, reducing the number of detectable cancerous growths in a population of patients receiving a prophylactic treatment relative to an untreated control population, and/or delaying the appearance of detectable cancerous growths in a treated population versus an untreated control population, e.g., by a statistically and/or clinically significant amount.
  • administering or “administration of’ a substance, a compound or an agent to a subject can be carried out using one of a variety of methods known to those skilled in the art.
  • a compound or an agent can be administered, intravenously, arterially, intradermally, intramuscularly, intraperitoneally, subcutaneously, ocularly, sublingually, orally (by ingestion), intranasally (by inhalation), intraspinally, intracerebrally, and transdermally (by absorption, e.g., through a skin duct).
  • a compound or agent can also appropriately be introduced by rechargeable or biodegradable polymeric devices or other devices, e.g., patches and pumps, or formulations, which provide for the extended, slow or controlled release of the compound or agent.
  • Administering can also be performed, for example, once, a plurality of times, and/or over one or more extended periods.
  • a compound or an agent is administered orally, e.g., to a subject by ingestion.
  • the orally administered compound or agent is in an extended release or slow release formulation, or administered using a device for such slow or extended release.
  • the phrase “conjoint administration” refers to any form of administration of two or more different therapeutic agents such that the second agent is administered while the previously administered therapeutic agent is still effective in the body (e.g., the two agents are simultaneously effective in the patient, which may include synergistic effects of the two agents).
  • the different therapeutic compounds can be administered either in the same formulation or in separate formulations, either concomitantly or sequentially.
  • an individual who receives such treatment can benefit from a combined effect of different therapeutic agents.
  • a “therapeutically effective amount” or a “therapeutically effective dose” of a drug or agent is an amount of a drug or an agent that, when administered to a subject, will have the intended therapeutic effect.
  • the full therapeutic effect does not necessarily occur by administration of one dose, and may occur only after administration of a series of doses.
  • a therapeutically effective amount may be administered in one or more administrations.
  • the precise effective amount needed for a subject will depend upon, for example, the subject’s size, health and age, and the nature and extent of the condition being treated, such as cancer or MDS. The skilled worker can readily determine the effective amount for a given situation by routine experimentation.
  • acyl is art-recognized and refers to a group represented by the general formula hydrocarbylC(O)-, preferably alkylC(O)-.
  • acylamino is art-recognized and refers to an amino group substituted with an acyl group and may be represented, for example, by the formula hydrocarbylC(O)NH-.
  • acyloxy is art-recognized and refers to a group represented by the general formula hydrocarbylC(O)O-, preferably alkylC(O)O-.
  • alkoxy refers to an alkyl group having an oxygen attached thereto.
  • Representative alkoxy groups include methoxy, ethoxy, propoxy, tert-butoxy and the like.
  • alkoxyalkyl refers to an alkyl group substituted with an alkoxy group and may be represented by the general formula alkyl-O-alkyl.
  • alkyl refers to saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl-substituted cycloalkyl groups, and cycloalkyl-substituted alkyl groups.
  • a straight chain or branched chain alkyl has 30 or fewer carbon atoms in its backbone (e.g., Ci- 30 for straight chains, C3-30 for branched chains), and more preferably 20 or fewer.
  • alkyl as used throughout the specification, examples, and claims is intended to include both unsubstituted and substituted alkyl groups, the latter of which refers to alkyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone, including haloalkyl groups such as trifluoromethyl and 2,2,2- trifluoroethyl, etc.
  • C x.y or “C x -C y ”, when used in conjunction with a chemical moiety, such as, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is meant to include groups that contain from x to y carbons in the chain.
  • Coalkyl indicates a hydrogen where the group is in a terminal position, a bond if internal.
  • a Ci-ealkyl group for example, contains from one to six carbon atoms in the chain.
  • alkylamino refers to an amino group substituted with at least one alkyl group.
  • alkylthio refers to a thiol group substituted with an alkyl group and may be represented by the general formula alkylS-.
  • amide refers to a group wherein R 9 and R 10 each independently represent a hydrogen or hydrocarbyl group, or R 9 and R 10 taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure.
  • amine and “amino” are art-recognized and refer to both unsubstituted and substituted amines and salts thereof, e.g., a moiety that can be represented by wherein R 9 , R 10 , and R 10 ’ each independently represent a hydrogen or a hydrocarbyl group, or R 9 and R 10 taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure.
  • aminoalkyl refers to an alkyl group substituted with an amino group.
  • aralkyl refers to an alkyl group substituted with an aryl group.
  • aryl as used herein include substituted or unsubstituted single-ring aromatic groups in which each atom of the ring is carbon.
  • the ring is a 5- to 7- membered ring, more preferably a 6-membered ring.
  • aryl also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is aromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls.
  • Aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, and the like.
  • carboxylate is art-recognized and refers to a group wherein R 9 and R 10 independently represent hydrogen or a hydrocarbyl group.
  • Carbocyclylalkyl refers to an alkyl group substituted with a carbocycle group.
  • carbocycle refers to a non-aromatic saturated or unsaturated ring in which each atom of the ring is carbon.
  • a carbocycle ring contains from 3 to 10 atoms, more preferably from 5 to 7 atoms.
  • Carbocyclylalkyl refers to an alkyl group substituted with a carbocycle group.
  • carbonate is art-recognized and refers to a group -OCO2-.
  • esters refers to a group -C(O)OR 9 wherein R 9 represents a hydrocarbyl group.
  • ether refers to a hydrocarbyl group linked through an oxygen to another hydrocarbyl group. Accordingly, an ether substituent of a hydrocarbyl group may be hydrocarbyl-O-. Ethers may be either symmetrical or unsymmetrical. Examples of ethers include, but are not limited to, heterocycle-O-heterocycle and aryl-O- heterocycle. Ethers include “alkoxyalkyl” groups, which may be represented by the general formula alkyl-O-alkyl.
  • halo and “halogen” as used herein means halogen and includes chloro, fluoro, bromo, and iodo.
  • heteroalkyl and “heteroaralkyl”, as used herein, refers to an alkyl group substituted with a hetaryl group.
  • heteroaryl and “hetaryl” include substituted or unsubstituted aromatic single ring structures, preferably 5- to 7-membered rings, more preferably 5- to 6-membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms.
  • heteroaryl and “hetaryl” also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is heteroaromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls.
  • Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine, and the like.
  • heteroatom as used herein means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, and sulfur.
  • heterocyclylalkyl refers to an alkyl group substituted with a heterocycle group.
  • heterocyclyl refers to substituted or unsubstituted non-aromatic ring structures, preferably 3- to 10-membered rings, more preferably 3- to 7-membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms.
  • heterocyclyl and “heterocyclic” also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is heterocyclic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls.
  • Heterocyclyl groups include, for example, piperidine, piperazine, pyrrolidine, morpholine, lactones, lactams, and the like.
  • Hydrocarbyl groups include, but are not limited to aryl, heteroaryl, carbocycle, heterocycle, alkyl, alkenyl, alkynyl, and combinations thereof.
  • hydroxy alkyl refers to an alkyl group substituted with a hydroxy group.
  • lower when used in conjunction with a chemical moiety, such as, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is meant to include groups where there are ten or fewer atoms in the substituent, preferably six or fewer.
  • acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy substituents defined herein are respectively lower acyl, lower acyloxy, lower alkyl, lower alkenyl, lower alkynyl, or lower alkoxy, whether they appear alone or in combination with other substituents, such as in the recitations hydroxyalkyl and aralkyl (in which case, for example, the atoms within the aryl group are not counted when counting the carbon atoms in the alkyl substituent).
  • polycyclyl refers to two or more rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls) in which two or more atoms are common to two adjoining rings, e.g., the rings are “fused rings”.
  • Each of the rings of the polycycle can be substituted or unsubstituted.
  • each ring of the polycycle contains from 3 to 10 atoms in the ring, preferably from 5 to 7.
  • sulfate is art-recognized and refers to the group -OSO3H, or a pharmaceutically acceptable salt thereof.
  • sulfonamide is art-recognized and refers to the group represented by the general formulae wherein R 9 and R 10 independently represents hydrogen or hydrocarbyl.
  • sulfoxide is art-recognized and refers to the group-S(O)-.
  • sulfonate is art-recognized and refers to the group SO3H, or a pharmaceutically acceptable salt thereof.
  • substituted refers to moieties having substituents replacing a hydrogen on one or more carbons of the backbone. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds.
  • the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds.
  • the permissible substituents can be one or more and the same or different for appropriate organic compounds.
  • the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms.
  • Substituents can include any substituents described herein, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxyl, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic mo
  • thioalkyl refers to an alkyl group substituted with a thiol group.
  • thioester refers to a group -C(O)SR 9 or -SC(O)R 9 wherein R 9 represents a hydrocarbyl.
  • thioether is equivalent to an ether, wherein the oxygen is replaced with a sulfur.
  • urea is art-recognized and may be represented by the general formula wherein R 9 and R 10 independently represent hydrogen or a hydrocarbyl.
  • modulate includes the inhibition or suppression of a function or activity (such as cell proliferation) as well as the enhancement of a function or activity.
  • compositions, excipients, adjuvants, polymers and other materials and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • “Pharmaceutically acceptable salt” or “salt” is used herein to refer to an acid addition salt or a basic addition salt which is suitable for or compatible with the treatment of patients.
  • pharmaceutically acceptable acid addition salt means any non-toxic organic or inorganic salt of any base compounds represented by formula I or II.
  • Illustrative inorganic acids which form suitable salts include hydrochloric, hydrobromic, sulfuric and phosphoric acids, as well as metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate.
  • Illustrative organic acids that form suitable salts include mono-, di-, and tricarboxylic acids such as glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, benzoic, phenylacetic, cinnamic and salicylic acids, as well as sulfonic acids such as p-toluene sulfonic and methanesulfonic acids. Either the mono or di-acid salts can be formed, and such salts may exist in either a hydrated, solvated or substantially anhydrous form.
  • mono-, di-, and tricarboxylic acids such as glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, benzoic, phenylacetic, cinnamic and salicylic acids, as well as sul
  • the acid addition salts of compounds of formula I or II are more soluble in water and various hydrophilic organic solvents, and generally demonstrate higher melting points in comparison to their free base forms.
  • the selection of the appropriate salt will be known to one skilled in the art.
  • Other non-pharmaceutically acceptable salts e.g., oxalates, may be used, for example, in the isolation of compounds of formula I or II for laboratory use, or for subsequent conversion to a pharmaceutically acceptable acid addition salt.
  • pharmaceutically acceptable basic addition salt means any non-toxic organic or inorganic base addition salt of any acid compounds represented by formula I or II or any of their intermediates.
  • Illustrative inorganic bases which form suitable salts include lithium, sodium, potassium, calcium, magnesium, or barium hydroxide.
  • Illustrative organic bases which form suitable salts include aliphatic, alicyclic, or aromatic organic amines such as methylamine, trimethylamine and picoline or ammonia. The selection of the appropriate salt will be known to a person skilled in the art.
  • stereogenic center in their structure.
  • This stereogenic center may be present in a R or a S configuration, said R and S notation is used in correspondence with the rules described in Pure Appl. Chem. (1976), 45, 11-30.
  • the disclosure contemplates all stereoisomeric forms such as enantiomeric and diastereoisomeric forms of the compounds, salts, prodrugs or mixtures thereof (including all possible mixtures of stereoisomers). See, e.g., WO 01/062726.
  • Prodrug or “pharmaceutically acceptable prodrug” refers to a compound that is metabolized, for example hydrolyzed or oxidized, in the host after administration to form the compound of the present disclosure (e.g., compounds of formula I or II ).
  • Typical examples of prodrugs include compounds that have biologically labile or cleavable (protecting) groups on a functional moiety of the active compound.
  • Prodrugs include compounds that can be oxidized, reduced, aminated, deaminated, hydroxylated, dehydroxylated, hydrolyzed, dehydrolyzed, alkylated, dealkylated, acylated, deacylated, phosphorylated, or dephosphorylated to produce the active compound.
  • Examples of prodrugs using ester or phosphoramidate as biologically labile or cleavable (protecting) groups are disclosed in U.S. Patents 6,875,751, 7,585,851, and 7,964,580, the disclosures of which are incorporated herein by reference.
  • the prodrugs of this disclosure are metabolized to produce a compound of formula I or II .
  • the present disclosure includes within its scope, prodrugs of the compounds described herein. Conventional procedures for the selection and preparation of suitable prodrugs are described, for example, in “Design of Prodrugs” Ed. H. Bundgaard, Elsevier, 1985.
  • Log of solubility is used in the art to quantify the aqueous solubility of a compound.
  • the aqueous solubility of a compound significantly affects its absorption and distribution characteristics. A low solubility often goes along with a poor absorption.
  • LogS value is a unit stripped logarithm (base 10) of the solubility measured in mol/liter.
  • Example 1 In vivo effect of MPC inhibition
  • the frailty index used included visible quantification of skin, eyes, muscle tone, lethargy, weight, etc., and is based on previously published models showing that frailty index of mouse closely mimics that of human. As shown in Figure 10, mice fed chow with UK5099 displayed an improved frailty index over both short and long time courses.
  • liver tumors were diminished in aged mice treated with UK5099 could signal a change in liver physiology.
  • two previous studies showed that genetic deletion of Mpcl or Mpc2 specifically in the liver blocked pyruvate oxidation and improved glucose tolerance in young mice.
  • aged mice showed strong signs of steathosis, or fatty liver disease (FLD) (Fig 4).
  • Liver tissue was harvested from young, aged and aged animals treated with UK5099 at 2.25 years of age, and 3 months of treatment with control or UK5099 chow. Tissue samples were prepared mass spectrometry by lysing and methanol extraction. Metabolomics analysis was performed on a mass spec instrument, and relative levels of the indicated metabolites were assessed ( Figure 17). In most cases, metabolite levels differed between young and old, and most of these changes were reversed by UK5099 treatment. Analysis was performed on at least 4 samples per condition, the mean of each condition is plotted.
  • Liver tissue was harvested from young, aged and aged animals treated with UK5099 at 2.25 years of age, and 3 months of treatment with control or UK5099 chow. Tissue samples were prepared mass spectrometry by lysing and methanol extraction. Metabolomics analysis was performed on a mass spec instrument, and relative levels of the indicated metabolites were assessed ( Figure 21). In most cases, metabolite levels differed between young and old, and most of these changes were reversed by UK5099 treatment. This was particularly notable for lipids, considering the fatty liver phenotype.

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Abstract

La présente divulgation concerne des procédés d'inhibition systémique de la protéine porteuse de pyruvate mitochondrial comprenant l'administration systémique d'un inhibiteur-transporteur de pyruvate mitochondrial à un patient. L'invention concerne en outre des procédés pour induire l'activation de cellules souches adultes dans un tissu vieilli ; réduire au moins un signe de vieillissement ; favoriser la pousse des cheveux ; ou inhiber la tumorigenèse induite par l'âge, comprenant l'administration systémique à un patient d'un inhibiteur de MFC.
PCT/US2025/014294 2024-02-01 2025-02-03 Inhibition de mpc systémique pour inverser les signes de vieillissement Pending WO2025166338A2 (fr)

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