Systemic MPC inhibition to reverse signs of aging

Abstract

The present disclosure relates to methods of systemic inhibition of the mitochondrial pyruvate carrier protein comprising systemic administration of a mitochondrial pyruvate carrier inhibitor to a patient. The disclosure further relates to methods of inducing adult stem cell activation in an aged tissue; reducing at least one sign of aging; promoting hair growth; or inhibiting age-induced tumorigenesis, comprising systemically administering to a patient an MFC inhibitor.

Description

[0001] SYSTEMIC MPC INHIBITION TO REVERSE SIGNS OF AGING

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims the benefit of U.S. provisional Patent Application No. 63 / 548,704, filed February 1, 2024, which is incorporated by reference herein in its entirety.

[0004] BACKGROUND

[0005] While nearly every tissue appears to set aside a population of stem cells for regeneration due to turnover or injury, these cells lose the capacity to activate regeneration upon aging. This is exemplified in the skin where hair follicle stem cells are known to reside throughout the life of the tissue, even during age-induced alopecia or hair loss. Most tissues are organized similarly whereby stem or progenitor cells are set aside and only activated during periodic tissue regeneration in response to normal turnover (intestine, skin, esophagus, etc.) or injury (muscle, brain, blood). Therefore, potentially all tissues could benefit from rejuvenation of adult stem cells which are known to decrease their activity with aging.

[0006] Hair follicle stem cells (HFSCs) undergo successive rounds of quiescence (telogen) punctuated by brief periods of proliferation correlating with the start of the hair cycle (telogen- anagen transition). Proliferation or activation of HFSCs is well known to be a prerequisite for advancement of the hair cycle. Despite advances in treatment options, 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.

[0007] Additional therapies are needed to reduce the signs of aging.

[0008] SUMMARY OF THE INVENTION

[0009] In certain aspects, 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. In some embodiments, the at least one sign of aging comprises morbidity, slowed, hair cycle, hair graying, ocular occlusion, mobility, kyphosis, cognitive impairment, or any combination thereof.

[0010] In some embodiments, the patient has baldness or alopecia.

[0011] In some embodiments, 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.

[0012] In some embodiments, the age-induced tumorigenesis is tumorigenesis in skin, liver, kidney, fat, or a combination thereof. In more particular embodiments, the tumorigenesis in skin is melanoma.

[0013] The MPC inhibitor may be administered orally, intravenously, or parenterally. In certain preferred embodiments, the MPC inhibitor is administered orally.

[0014] In certain aspects, 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.

[0015] In certain aspects, 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, CR4, or N;

[0016] OR10

[0017] - -P — OR10Ml

[0018] Y is carboxyl, ester, amide, or ° Z is CH, CR4, or N;

[0019] R2is CN or carboxyl;

[0020] R3is aralkyl or aralkylacyl, wherein R3is substituted by two R5in the meta positions, wherein each R5is independently selected from alkyl, alkoxy, or halo; each R4is independently alkyl, carboxyl, halo, hydroxy, ester, or CN;

[0021] R7is hydrogen, alkyl, halo, hydroxyl, alkoxy, or acyloxy;

[0022] R10is hydrogen or alkyl; and n is 0-4; or a pharmaceutically acceptable salt thereof.

[0023] BRIEF DESCRIPTION OF THE DRAWINGS

[0024] 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.

[0025] Figures 2A-2C. Systemic inhibition of pyruvate oxidation by Mpc inhibition improves the frailty index in aged mice. We modified an established frailty index to measure visible signs of aging in mice starting at two years of age. 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.

[0026] Figure 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.

[0027] Figure 3B shows photographic images of hair growth in mice treated with vehicle and with UK5099.

[0028] Figure 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.

[0029] Figure 5. Assay for senescence in peripheral fat. We used the |3-gal assay on fat from young (top row) and aged mice treated with vehicle (middle row), or UK5099 (bottom). This experiment revealed a paradoxical induction of senescence by UK5099 in fat, but a distinct result in other tissues (not shown). While we had expected the opposite result, this could potentially explain why tumorigenesis was abrogated in UK5099 treated animals.

[0030] Figure 6. Mpc inhibition by UK5099 restores a youthful appearance to adipose tissue in aged animals. Left, histology of visceral fat from young animals. Middle, histology of visceral fat from aged animals (+2 years). Right, histology of visceral fat from aged animals after 6 months of treatment with UK5099.

[0031] Figure 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.

[0032] 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.

[0033] Figure 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.

[0034] Figure 9. The Aging Experiment Workflow in modeling adult stem cell exhaustion in mice.

[0035] Figure 10. The effect of UK5099 on frailty index over time.

[0036] Figure 11. The effect of UK5099 on overall lifespan.

[0037] Figure 12. The effect of UK5099 on overall weight.

[0038] Figure 13A. Systemic MPC inhibition and effect on hair cycle. Images of mice treated with UK5099.

[0039] Figure 13B. Systemic MPC inhibition and effect on hair cycle. Epidermis thickness of mice treated with UK5099.

[0040] Figure 14A. Hair growth over time in mice with low, medium, and high doses of UK- 5099.

[0041] Figure 14B. New hair growth over time in mice treated with low, medium, and high doses of UK-5099.

[0042] Figure 15A. Effect of chronic MPC inhibition on adipose tissue. Images of fat tissue in male and female mice treated with UK5099.

[0043] Figure 15B. Effect of chronic MPC inhibition on adipose tissue. Fat cell area of mice treated with low, medium, and high doses of UK5099.

[0044] Figure 16. Chronic MPC inhibition in aged liver.

[0045] Figure 17. Metabolomic assessment of old mice treated with UK5099.

[0046] 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.

[0047] Figure 19. The effect of UK5099 on liver nucleotides in aged mice.

[0048] Figure 20. The effect of UK5099 on liver amino acids in aged mice.

[0049] Figure 21. Lipid metabolomic assessment of old mice treated with UK5099.

[0050] DETAILED DESCRIPTION OF THE INVENTION

[0051] 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. On the other hand, fewer 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.

[0052] We and others have shown that inhibition of pyruvate oxidation can promote activation of adult stem cells in the skin, gut and brain. Our preliminary data suggest that systemic administration of a small molecule inhibitor of pyruvate oxidation is capable of rejuvenating adult stem cells in aging hair follicles, and potentially other tissues as well.

[0053] 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.

[0054] The present methods may advantageously promote regeneration and prevent tumorigenesis during aging.

[0055] While nearly every tissue appears to set aside a population of stem cells for regeneration due to turnover or injury, these cells are known to lose the capacity to activate regeneration upon aging. This is exemplified in the skin where hair follicle stem cells are known to reside throughout the life of the tissue, even during age-induced alopecia or hair loss. Most tissues are organized similarly whereby stem or progenitor cells are set aside and only activated during periodic tissue regeneration in response to normal turnover (intestine, skin, esophagus, etc.) or injury (muscle, brain, blood). Therefore, potentially all tissues could benefit from rejuvenation of adult stem cells which are known to decrease their activity with aging. Our previous studies have shown that activation of hair follicle stem cells in aged animals is possible through metabolic manipulation. Whether the same is possible for other tissues is unknown but most tissues are thought to retain their stem cell populations during aging.

[0056] Over the last 10 years we have identified metabolic pathways that are specifically enriched in hair follicle stem cells and showed that manipulation of these pathways can strongly regulate hair follicle stem cell activation. Most notably, we showed in two studies that topical inhibition of pyruvate oxidation by distinct mechanisms can re-activate dormant hair follicle stem cells in aged mice to re-initiate a hair cycle. Furthermore, we have carried out unpublished studies showing that deletion of Mpcl in murine neural stem cells also leads to their activation, and this result was bolstered by a recent publication from another group showing an identical effect. In addition, others have argued that other types of adult stem cells found in distinct tissues such as the intestine could be subject to the same type of metabolic regulation that we discovered in the skin. On the other hand, perhaps not every tissue stem cell is subject to such regulation as we have data showing the melanocyte stem cell homeostasis does not appear to be affected by deletion of Mpcl (Seyran et al., in preparation, not shown). None of these previous studies attempted to systemically manipulate metabolism in adult stem cells with the purpose of reversing signs of aging in an animal model. We hypothesize that many (but not all) adult stem cells in various tissues share enrichment for glycolytic metabolism that we observed in HFSCs, and therefore would respond to inhibition of pyruvate oxidation in a similar manner. Therefore, it is believed that systemically administering regulators of pyruvate oxidation in aged mice or genetically blocking pyruvate oxidation in will drive adult stem cells to awaken and promote regeneration in their resident tissue.

[0057] In certain aspects, 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.

[0058] In some embodiments, the at least one sign of aging comprises morbidity, slowed, hair cycle, hair graying, ocular occlusion, mobility, kyphosis, cognitive impairment, or any combination thereof.

[0059] 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.

[0060] Frailty Index (FI) = (number of health deficits present) (number of health deficits measured)

[0061] In some embodiments, the patient has baldness or alopecia.

[0062] In some embodiments, 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.

[0063] In some embodiments, the age-induced tumorigenesis is tumorigenesis in skin, liver, kidney, fat, or a combination thereof. In more particular embodiments, 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.

[0064] In certain aspects, 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. In certain embodiments, 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. In certain embodiments, the method comprises systemically inhibiting a mitochondrial pyruvate carrier (MPC) protein. In certain embodiments, the method comprises inducing adult stem cell activation in an aged tissue. In certain embodiments, the method comprises reducing at least one sign of aging. In certain embodiments, the method comprises promoting hair growth. In certain embodiments, the method comprises inhibiting age-induced tumorigenesis. In certain embodiments, the method comprises treating fatty liver disease. In certain embodiments, the method comprises treating or slowing muscle wastage.

[0065] In certain embodiments, the MPC inhibitor is a compound of formula I or II, wherein: each A is independently CH, CR4, or N;

[0066] OR10

[0067] - -P — OR10l

[0068] Y is carboxyl, ester, amide, or ° ;

[0069] Z is CH, CR4, or N.

[0070] R2is CN or carboxyl;

[0071] R3is H, aryl, aralkyl, or aralkylacyl, and is optionally substituted by one or more R5, wherein each R5is independently selected from alkyl, alkoxy, or halo; each instance of R4is independently alkyl, carboxyl, halo, hydroxy, ester, or CN;

[0072] R7is hydrogen, alkyl, halo, hydroxyl, alkoxy, or acyloxy;

[0073] R10is hydrogen or alkyl; and n is 0-4; or a pharmaceutically acceptable salt thereof.

[0074] In certain embodiments, Z is CH or N. In certain embodiments, the compound is a compound of formula III, wherein,

[0075] OR10

[0076] - -P — OR10Ml

[0077] Y is carboxyl, ester, amide, or O ;

[0078] R2is CN or carboxyl;

[0079] R3is H, aryl, aralkyl, or aralkylacyl, and is optionally substituted by one or more R5, wherein each R5is independently selected from alkyl, alkoxy, or halo; each instance of R4is independently alkyl, carboxyl, halo, hydroxy, ester, or CN;

[0080] R6is from H, alkyl, or cycloalkyl; and

[0081] R7is hydrogen, alkyl, halo, hydroxyl, alkoxy, or acyloxy;

[0082] R10is hydrogen or alkyl

[0083] R11is H or alkyl; and n is 0-4; or a pharmaceutically acceptable salt thereof.

[0084] OR10

[0085] - -P — OR10Ml In certain embodiments, Y is ° . In certain embodiments, R10is H. In certain embodiments, R10is alkyl (e.g ethyl). In certain embodiments, Y is ester or amide. In certain embodiments, R11is alkyl (e.g., methyl).

[0086] In certain embodiments, the MPC inhibitor is a compound of formula V, VI, or VII, wherein: each A is independently CH, CR4, or N;

[0087] X is NR6or O; R1is H or lower alkyl; or either R1and R6or R1and R2, together with the atoms that separate them, complete a heterocycle;

[0088] R2is CN or carboxyl;

[0089] R3is H, aryl, aralkyl, or aralkylacyl, and is optionally substituted by one or more R5, wherein each R5is independently selected from alkyl, alkoxy, or halo; each instance of R4is independently alkyl, carboxyl, halo, hydroxy, or CN;

[0090] R6is from H, alkyl, or cycloalkyl;

[0091] R7is hydrogen, alkyl, halo, hydroxyl, alkoxy, or acyloxy; and n is 0-4; or a pharmaceutically acceptable salt thereof.

[0092] In certain embodiments, at least one A is N. In certain embodiments, exactly one A is

[0093] N.

[0094] In certain embodiments, the MPC inhibitor is a compound of formula Va, Via, or

[0095] Vila: wherein:

[0096] X is NR6or O;

[0097] R1is H or lower alkyl;

[0098] R2is CN or carboxyl; or R1and R2, together with the atoms that separate them, complete a heterocycle;

[0099] R3is H, phenyl, or benzyl, and is optionally substituted by one or more R5, wherein each R5is independently selected from alkyl, alkoxy, or halo; each instance of R4is independently selected from alkyl, carboxyl, halo, hydroxy, or CN;

[0100] R6is selected from H, alkyl, or cycloalkyl; and n is 0-4; or a pharmaceutically acceptable salt thereof.

[0101] In certain embodiments, X is NH. In certain embodiments, X is O.

[0102] In certain embodiments, R1is H. In certain embodiments, R1is lower alkyl.

[0103] In certain embodiments, R1and R6, together with the atoms that separate them, complete a heterocycle (e.g., morpholinyl). In certain embodiments, R6is hydrogen. In certain embodiments, R2is CN. In certain embodiments, R2is carboxyl.

[0104] In certain embodiments, R1and R2, 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.

[0105] In certain embodiments, the MPC inhibitor is a compound of formula Va.

[0106] In certain embodiments, the MPC inhibitor is a compound of formula Via.

[0107] In certain embodiments, R3is H. In certain embodiments, R3is phenyl. In certain embodiments, R3is phenyl and is substituted by one or more R5. In certain embodiments, R3is substituted by one R5, and wherein R5is an alkoxy. In certain embodiments, R3is aralkyl (e.g., benzyl or phenethyl). In certain embodiments, R3is aralkyl. In certain embodiments, R3is aralkylacyl (e.g., phenylacetyl). In certain embodiments, R3is benzyl. In certain embodiments, R3is benzyl and is substituted by one or more R5. In certain embodiments, R3is aralkyl (e.g., benzyl or phenethyl) and is substituted by one or more R5(preferably on the phenyl ring). In certain embodiments, R3is aralkylacyl (e.g., phenylacetyl), and is substituted by one or more R5(preferably on the phenyl ring). In certain embodiments, R3is substituted by one or two R5, wherein each R5is independently selected from fluoroalkyl or fluoro. In certain embodiments, R3is substituted by two R5, and wherein each R5is independently selected from fluoroalkyl or fluoro. In certain embodiments, R3is substituted by two R5, wherein each R5is trifluoromethyl. In certain embodiments, R3is substituted by two R5in the meta positions, wherein each R5is trifluoromethyl.

[0108] In certain embodiments, the MPC inhibitor is a compound of formula Vb: certain embodiments, n is 0.

[0109] In certain embodiments, the MPC inhibitor is a compound of formula Vc: certain embodiments, n is 1.

[0110] In certain embodiments, the MPC inhibitor is a compound of formula Vd:

[0111] In certain embodiments, R4is selected from halo or haloalkyl. In certain embodiments, R4is halo (e.g., chloro or bromo).

[0112] In certain embodiments, the compound is of formula VI.

[0113] In certain embodiments, the compound is of formula Via.

[0114] In certain embodiments, n is 0.

[0115] In certain embodiments, n is 2, and R4is selected from halo or haloalkyl.

[0116] In certain embodiments, the compound is of formula VII.

[0117] In certain embodiments, the compound is of formula Vila.

[0118] In certain embodiments, R7is hydrogen, hydroxyl, halo (e.g., chloro), or acyloxy (e.g., acetyloxy). In certain embodiments, R7is hydroxyl, halo (e.g., chloro), or acyloxy (e.g., acetyloxy).

[0119] In certain embodiments, the MPC inhibitor is selected from

[0120]

[0121]

[0122] JXL032 JXL033 JXL034 JXL035 or a pharmaceutically acceptable salt thereof.

[0123] In certain embodiments, the MPC inhibitor is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein:

[0124] Y is carboxyl, ester, amide,

[0125] R1is H, aryl, aralkyl, or aralkylacyl, and is optionally substituted by one or more R5;

[0126] R2is CN or carboxyl;

[0127] R4is independently alkyl, alkenyl, alkynyl, azido, halo, hydroxy, carboxyl, ester, or CN;

[0128] R5is independently selected from alkyl, alkoxy, or halo; and n is 0-4.

[0129] In certain embodiments,

[0130] In certain embodiments, R10is H. In certain embodiments, R10is alkyl (e.g., ethyl).

[0131] In certain embodiments, Y is ester or carboxyl.

[0132] In certain embodiments, R2is CN. In certain embodiments, R2is carboxyl.

[0133] In certain embodiments, R1is H. In certain embodiments, R1is aralkyl (e.g., benzyl or phenethyl). In certain embodiments, R1is aralkyl (e.g., benzyl or phenethyl) and is substituted by one or more R5(preferably on the phenyl ring). In certain embodiments, R1is aralkylacyl (e.g., phenylacetyl), and is substituted by one or more R5(preferably on the phenyl ring). In certain embodiments, R1is substituted by one or two R5, and wherein each R5is independently selected from fluoroalkyl or fluoro. In certain embodiments, R1is substituted by two R5, and wherein each R5is trifluoromethyl.

[0134] In certain embodiments, R4is 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, R4is not chloro or bromo.

[0135] In certain embodiments, the MPC inhibitor is a compound of formula la: wherein R6is H, alkyl, aryl, or aralkyl.

[0136] In certain embodiments, the MPC inhibitor is selected from: pharmaceutically acceptable salt thereof.

[0137] In certain embodiments, the at least one sign of aging comprises morbidity, slowed hair cycle, hair graying, ocular occlusion, mobility, kyphosis, cognitive impairment, or any combination thereof. In certain embodiments, the patient has baldness or alopecia. In certain embodiments, 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. In certain embodiments, the age-induced tumorigenesis is tumorigenesis in skin, liver, kidney, fat, or a combination thereof. In certain embodiments, the tumorigenesis in skin is melanoma. In certain embodiments, the MPC inhibitor is administered orally. In certain embodiments, the MPC inhibitor is administered intravenously. In certain embodiments, the MPC inhibitor is administered parenterally.

[0138] In certain embodiments, 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.

[0139] In certain embodiments, the MPC inhibitor is administered daily.

[0140] In certain embodiments, 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. 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 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. 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 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.

[0141] 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 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. 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 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.

[0142] 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 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. 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 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.

[0143] 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 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. 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 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.

[0144] In certain embodiments, following systemic administration of the MPC inhibitor, 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.

[0145] In certain aspects, 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, CR4, or N;

[0146] OR10

[0147] - -P — OR10l

[0148] Y is carboxyl, ester, amide, or °

[0149] Z is CH, CR4, or N. R2is CN or carboxyl;

[0150] R3is aralkyl or aralkylacyl, wherein R3is substituted by two R5in the meta positions, wherein each R5is independently selected from alkyl, alkoxy, or halo; each R4is independently alkyl, carboxyl, halo, hydroxy, ester, or CN;

[0151] R7is hydrogen, alkyl, halo, hydroxyl, alkoxy, or acyloxy;

[0152] R10is hydrogen or alkyl; and n is 0-4; or a pharmaceutically acceptable salt thereof.

[0153] In certain embodiments, Z is CH or N.

[0154] In certain embodiments, the MPC inhibitor is a compound of formula III, wherein,

[0155] OR10

[0156] - -P — OR10Ml

[0157] Y is carboxyl, ester, amide, or ° ;

[0158] R2is CN or carboxyl;

[0159] R3is aralkyl or aralkylacyl, wherein R3is substituted by two R5in the meta positions, wherein each R5is independently selected from alkyl, alkoxy, or halo; each R4is independently alkyl, carboxyl, halo, hydroxy, ester, or CN;

[0160] R7is hydrogen, alkyl, halo, hydroxyl, alkoxy, or acyloxy; and

[0161] R10is hydrogen or alkyl; or a pharmaceutically acceptable salt thereof.

[0162] OR10

[0163] - -P — OR10Ml

[0164] In certain embodiments, Y is O . In certain such embodiments, R10is H. In other such embodiments, R10is alkyl (e.g., ethyl). In certain embodiments, Y is ester or amide.

[0165] In certain embodiments, the MPC inhibitor is a compound of formula V, VI, or VII, wherein: each A is independently CH, CR4, or N;

[0166] X is NR6or O;

[0167] R1is H or lower alkyl; or either R1and R6or R1and R2, together with the atoms that separate them, complete a heterocycle;

[0168] R2is CN or carboxyl;

[0169] R3is aralkyl or aralkylacyl, wherein R3is substituted by two R5in the meta positions, wherein each R5is independently selected from alkyl, alkoxy, or halo; each R4is independently alkyl, carboxyl, halo, hydroxy, or CN;

[0170] R6is from H, alkyl, or cycloalkyl;

[0171] R7is hydrogen, alkyl, halo, hydroxyl, alkoxy, or acyloxy; and n is 0-4; or a pharmaceutically acceptable salt thereof.

[0172] In certain embodiments, at least one A is N. In certain embodiments, exactly one A is

[0173] N.

[0174] In certain embodiments, the MPC inhibitor is a compound of formula Va, Via, or

[0175] Vila: wherein:

[0176] X is NR6or O;

[0177] R1is H or lower alkyl;

[0178] R2is CN or carboxyl; or R1and R2, together with the atoms that separate them, complete a heterocycle;

[0179] R3is benzyl, wherein R3is substituted by two R5in the meta positions, wherein each R5is independently selected from alkyl, alkoxy, or halo; each R4is independently selected from alkyl, carboxyl, halo, hydroxy, or CN;

[0180] R6is selected from H, alkyl, or cycloalkyl; and n is 0-4; or a pharmaceutically acceptable salt thereof.

[0181] In certain embodiments, X is NH.

[0182] In certain embodiments, X is O. In certain embodiments, R1is H.

[0183] In certain embodiments, R1is lower alkyl. In certain embodiments, R1and R6, together with the atoms that separate them, complete a heterocycle (e.g., morpholinyl). In certain embodiments, R6is hydrogen.

[0184] In certain embodiments, R2is CN. In certain embodiments, R2is carboxyl. In certain embodiments, R1and R2, 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.

[0185] In certain embodiments, the compound is of formula Va.

[0186] In certain embodiments, the compound is of formula Via.

[0187] In certain embodiments, R3is aralkyl (e.g., benzyl or phenethyl). In certain embodiments, R3is aralkylacyl (e.g., phenylacetyl). In certain embodiments, R3is benzyl.

[0188] In certain embodiments, each R5is independently selected from fluoroalkyl or fluoro. In certain embodiments, each R5is trifluoromethyl.

[0189] In certain embodiments, the MPC inhibitor is a compound of formula Vb:

[0190] In certain embodiments, n is 0. In certain embodiments, n is 1.

[0191] In certain embodiments, the MPC inhibitor is a compound of formula Vd:

[0192] In certain embodiments, the MPC inhibitor is a compound of formula Ve:

[0193] In certain embodiments, R4is selected from halo or haloalkyl. In certain embodiments, R4is halo (e.g., chloro or bromo).

[0194] In certain embodiments, the MPC inhibitor is a compound of formula VI.

[0195] In certain embodiments, the MPC inhibitor is a compound of formula Via.

[0196] In certain embodiments, n is 0. In certain embodiments, n is 2, and R4is selected from halo or haloalkyl.

[0197] In certain embodiments, the MPC inhibitor is a compound of formula VII.

[0198] In certain embodiments, the MPC inhibitor is a compound of formula Vila.

[0199] In certain embodiments, R7is hydrogen, hydroxyl, halo (e.g., chloro), or acyloxy (e.g., acetyloxy). In certain embodiments, R7is hydroxyl, halo (e.g., chloro), or acyloxy (e.g., acetyloxy).

[0200] In certain embodiments, the MPC inhibitor is selected from

[0201] JXL032 JXL033 JXL034

[0202]

[0203] or a pharmaceutically acceptable salt thereof.

[0204] In certain embodiments, the MPC inhibitor is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein: OR10

[0205] - -P — OR10Ml

[0206] Y is carboxyl, ester, amide, or 0 ;

[0207] R1is aralkyl or aralkylacyl, wherein R3is substituted by two R5in the meta positions;

[0208] R2is CN or carboxyl; independently alkyl, alkenyl, alkynyl, azido, halo, hydroxy, carboxyl, ester, or CN; and is independently selected from alkyl, alkoxy, or halo.

[0209] OR10

[0210] - -P — OR10l In certain embodiments, Y is 0 . In certain such embodiments, R10is H. In other such embodiments, R10is alkyl (e.g., ethyl). In certain embodiments, Y is ester or carboxyl.

[0211] In certain embodiments, R2is CN. In certain embodiments, R2is carboxyl.

[0212] In certain embodiments, R1is aralkyl (e.g., benzyl or phenethyl). In certain embodiments, R1is aralkylacyl (e.g., phenylacetyl).

[0213] In certain embodiments, each R5is independently selected from fluoroalkyl or fluoro. In certain embodiments, each R5is trifluoromethyl.

[0214] In certain embodiments, R4is 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, R4is not chloro or bromo.

[0215] In certain embodiments, the MPC inhibitor is a compound of formula la: wherein R6is H, alkyl, aryl, or aralkyl,

[0216] In certain embodiments, the MPC inhibitor is selected from:

[0217] pharmaceutically acceptable salt thereof.

[0218] In certain embodiments, the nutritional supplement further comprises a multivitamin complex.

[0219] Pharmaceutical Compositions

[0220] The compounds described herein may be administered systemically as a pharmaceutical composition. In certain embodiments, the individual is a mammal such as a human, or a non-human mammal. When administered to an animal, such as a human, 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 are well known in the art and 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. In preferred embodiments, when such pharmaceutical compositions are for human administration, particularly for invasive routes of administration (i.e., routes, such as injection or implantation, that circumvent transport or diffusion through an epithelial barrier), 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.

[0221] 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. Such 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 (preparation) 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.

[0222] The phrase "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.

[0223] The phrase "pharmaceutically acceptable carrier" as used herein 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. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of 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 hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations.

[0224] A pharmaceutical composition (preparation) 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. In certain embodiments, a compound may be simply dissolved or suspended in sterile water. Details of appropriate routes of administration and compositions suitable for same can be found in, for example, U.S. Pat. Nos. 6,110,973, 5,763,493, 5,731,000, 5,541,231, 5,427,798, 5,358,970 and 4,172,896, as well as in patents cited therein.

[0225] 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.

[0226] 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. In general, 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.

[0227] 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.

[0228] To prepare solid dosage forms for oral administration (capsules (including sprinkle capsules and gelatin capsules), tablets, pills, dragees, powders, granules and the like), 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, such as, for example, cetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; (10) complexing agents, such as, modified and unmodified cyclodextrins; and (11) coloring agents. In the case of capsules (including sprinkle capsules and gelatin capsules), tablets and pills, the pharmaceutical 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.

[0229] 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.

[0230] The tablets, and other solid dosage forms of the pharmaceutical compositions, such as dragees, capsules (including sprinkle capsules and gelatin capsules), pills and granules, 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. They 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. Examples of 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.

[0231] Liquid dosage forms useful for oral administration include pharmaceutically acceptable emulsions, lyophiles for reconstitution, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, 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.

[0232] Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.

[0233] 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.

[0234] 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.

[0235] Transdermal patches have the added advantage of providing controlled delivery of a compound of the present invention to the body. Such 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.

[0236] The phrases "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. Pharmaceutical 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.

[0237] Examples of suitable aqueous and nonaqueous carriers that may be employed in the pharmaceutical compositions of the invention 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. 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.

[0238] These 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.

[0239] In some cases, 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.

[0240] 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.

[0241] For use in the methods of this invention, 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.

[0242] 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.

[0243] 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.

[0244] 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.

[0245] A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the therapeutically effective amount of the pharmaceutical composition required. For example, 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. By “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).

[0246] In general, 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.

[0247] If desired, 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. In certain embodiments of the present invention, the active compound may be administered two or three times daily. In preferred embodiments, the active compound will be administered once daily.

[0248] 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.

[0249] In certain embodiments, compounds of the invention may be used alone or conjointly administered with another type of therapeutic agent.

[0250] The present disclosure includes the use of pharmaceutically acceptable salts of compounds of the invention in the compositions and methods of the present invention. In certain embodiments, contemplated salts of the invention include, but are not limited to, alkyl, dialkyl, trialkyl or tetra-alkyl ammonium salts. In certain embodiments, 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. In certain embodiments, contemplated salts of the invention include, but are not limited to, Na, Ca, K, Mg, Zn or other metal salts. In certain embodiments, 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, ethane- 1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, d-glucoheptonic acid, d-gluconic acid, d-glucuronic acid, glutamic acid, glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, 1-malic acid, malonic acid, mandelic acid, methanesulfonic acid , naphthalene- 1,5-disulfonic acid, naphthalene-2- sulfonic acid, nicotinic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, proprionic acid, 1- pyroglutamic acid, salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, 1-tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid, and undecylenic acid salts.

[0251] 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.

[0252] Wetting agents, emulsifiers and lubricants, 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.

[0253] Examples of pharmaceutically acceptable antioxidants 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.

[0254] Definitions

[0255] Unless otherwise defined herein, scientific and technical terms used in this application shall have the meanings that are commonly understood by those of ordinary skill in the art. Generally, nomenclature used in connection with, and techniques of, chemistry, cell and tissue culture, molecular biology, cell and cancer biology, neurobiology, neurochemistry, virology, immunology, microbiology, pharmacology, genetics and protein and nucleic acid chemistry, described herein, are those well known and commonly used in the art. The methods and techniques of the present disclosure are generally performed, unless otherwise indicated, according to conventional methods well known in the art and as described in various general and more specific references that are cited and discussed throughout this specification. See, e.g. “Principles of Neural Science”, McGraw-Hill Medical, New York, N.Y. (2000); Motulsky, “Intuitive Biostatistics”, Oxford University Press, Inc. (1995); Lodish et al., “Molecular Cell Biology, 4th ed.”, W. H. Freeman & Co., New York (2000); Griffiths et al., “Introduction to Genetic Analysis, 7th ed.”, W. H. Freeman & Co., N.Y. (1999); and Gilbert et al., “Developmental Biology, 6th ed.”, Sinauer Associates, Inc., Sunderland, MA (2000).

[0256] Chemistry terms used herein, unless otherwise defined herein, are used according to conventional usage in the art, as exemplified by “The McGraw-Hill Dictionary of Chemical Terms”, Parker S., Ed., McGraw-Hill, San Francisco, C.A. (1985).

[0257] All of the above, and any other publications, patents and published patent applications referred to in this application are specifically incorporated by reference herein. In case of conflict, the present specification, including its specific definitions, will control.

[0258] The term “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.

[0259] 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).

[0260] “Treating” a condition or patient refers to taking steps to obtain beneficial or desired results, including clinical results. As used herein, and as well understood in the art, “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.

[0261] The term “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. Thus, 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.

[0262] “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. For example, 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.

[0263] Appropriate methods of administering a substance, a compound or an agent to a subject will also depend, for example, on the age and / or the physical condition of the subject and the chemical and biological properties of the compound or agent (e.g., solubility, digestibility, bioavailability, stability and toxicity). In some embodiments, a compound or an agent is administered orally, e.g., to a subject by ingestion. In some embodiments, 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.

[0264] As used herein, 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). For example, the different therapeutic compounds can be administered either in the same formulation or in separate formulations, either concomitantly or sequentially. Thus, an individual who receives such treatment can benefit from a combined effect of different therapeutic agents.

[0265] 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. Thus, 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.

[0266] The term “acyl” is art-recognized and refers to a group represented by the general formula hydrocarbylC(O)-, preferably alkylC(O)-.

[0267] The term “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-.

[0268] The term “acyloxy” is art-recognized and refers to a group represented by the general formula hydrocarbylC(O)O-, preferably alkylC(O)O-.

[0269] The term “alkoxy” refers to an alkyl group having an oxygen attached thereto. Representative alkoxy groups include methoxy, ethoxy, propoxy, tert-butoxy and the like.

[0270] The term “alkoxyalkyl” refers to an alkyl group substituted with an alkoxy group and may be represented by the general formula alkyl-O-alkyl.

[0271] The term “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. In preferred embodiments, 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.

[0272] Moreover, the term “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. The term “Cx.y” or “Cx-Cy”, 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.

[0273] The term “alkylamino”, as used herein, refers to an amino group substituted with at least one alkyl group.

[0274] The term “alkylthio”, as used herein, refers to a thiol group substituted with an alkyl group and may be represented by the general formula alkylS-.

[0275] The term “amide”, as used herein, refers to a group wherein R9and R10each independently represent a hydrogen or hydrocarbyl group, or R9and R10taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure.

[0276] The terms “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 R9, R10, and R10’ each independently represent a hydrogen or a hydrocarbyl group, or R9and R10taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure.

[0277] The term “aminoalkyl”, as used herein, refers to an alkyl group substituted with an amino group.

[0278] The term “aralkyl”, as used herein, refers to an alkyl group substituted with an aryl group.

[0279] The term “aryl” as used herein include substituted or unsubstituted single-ring aromatic groups in which each atom of the ring is carbon. Preferably the ring is a 5- to 7- membered ring, more preferably a 6-membered ring. The term “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.

[0280] The term “carbamate” is art-recognized and refers to a group wherein R9and R10independently represent hydrogen or a hydrocarbyl group.

[0281] The term “carbocyclylalkyl”, as used herein, refers to an alkyl group substituted with a carbocycle group.

[0282] The terms “carbocycle”, “carbocyclyl”, and “carbocyclic”, as used herein, refers to a non-aromatic saturated or unsaturated ring in which each atom of the ring is carbon. Preferably a carbocycle ring contains from 3 to 10 atoms, more preferably from 5 to 7 atoms.

[0283] The term “carbocyclylalkyl”, as used herein, refers to an alkyl group substituted with a carbocycle group.

[0284] The term “carbonate” is art-recognized and refers to a group -OCO2-.

[0285] The term “carboxy”, as used herein, refers to a group represented by the formula -CO2H.

[0286] The term “ester”, as used herein, refers to a group -C(O)OR9wherein R9represents a hydrocarbyl group.

[0287] The term “ether”, as used herein, 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.

[0288] The terms “halo” and “halogen” as used herein means halogen and includes chloro, fluoro, bromo, and iodo.

[0289] The terms “hetaralkyl” and “heteroaralkyl”, as used herein, refers to an alkyl group substituted with a hetaryl group.

[0290] The terms “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. The terms “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.

[0291] The term “heteroatom” as used herein means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, and sulfur.

[0292] The term “heterocyclylalkyl”, as used herein, refers to an alkyl group substituted with a heterocycle group.

[0293] The terms “heterocyclyl”, “heterocycle”, and “heterocyclic” refer 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. The terms “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.

[0294] The term “hydrocarbyl”, as used herein, refers to a group that is bonded through a carbon atom that does not have a =0 or =S substituent, and typically has at least one carbonhydrogen bond and a primarily carbon backbone, but may optionally include heteroatoms. Thus, groups like methyl, ethoxyethyl, 2-pyridyl, and even trifluoromethyl are considered to be hydrocarbyl for the purposes of this application, but substituents such as acetyl (which has a =0 substituent on the linking carbon) and ethoxy (which is linked through oxygen, not carbon) are not. Hydrocarbyl groups include, but are not limited to aryl, heteroaryl, carbocycle, heterocycle, alkyl, alkenyl, alkynyl, and combinations thereof.

[0295] The term “hydroxy alkyl”, as used herein, refers to an alkyl group substituted with a hydroxy group.

[0296] The term “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. A “lower alkyl”, for example, refers to an alkyl group that contains ten or fewer carbon atoms, preferably six or fewer. In certain embodiments, 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).

[0297] The terms “polycyclyl”, “polycycle”, and “polycyclic” refer 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. In certain embodiments, each ring of the polycycle contains from 3 to 10 atoms in the ring, preferably from 5 to 7.

[0298] The term “sulfate” is art-recognized and refers to the group -OSO3H, or a pharmaceutically acceptable salt thereof.

[0299] The term “sulfonamide” is art-recognized and refers to the group represented by the general formulae wherein R9and R10independently represents hydrogen or hydrocarbyl.

[0300] The term “sulfoxide” is art-recognized and refers to the group-S(O)-.

[0301] The term “sulfonate” is art-recognized and refers to the group SO3H, or a pharmaceutically acceptable salt thereof.

[0302] The term “sulfone” is art-recognized and refers to the group -S(O)2-.

[0303] The term “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. In a broad aspect, 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. For purposes of this invention, 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 moiety. It will be understood by those skilled in the art that the moieties substituted on the hydrocarbon chain can themselves be substituted, if appropriate.

[0304] The term “thioalkyl”, as used herein, refers to an alkyl group substituted with a thiol group.

[0305] The term “thioester”, as used herein, refers to a group -C(O)SR9or -SC(O)R9wherein R9represents a hydrocarbyl.

[0306] The term “thioether”, as used herein, is equivalent to an ether, wherein the oxygen is replaced with a sulfur.

[0307] The term “urea” is art-recognized and may be represented by the general formula wherein R9and R10independently represent hydrogen or a hydrocarbyl.

[0308] The term “modulate” as used herein includes the inhibition or suppression of a function or activity (such as cell proliferation) as well as the enhancement of a function or activity.

[0309] The phrase “pharmaceutically acceptable” is art-recognized. In certain embodiments, the term includes 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.

[0310] “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.

[0311] The term “pharmaceutically acceptable acid addition salt” as used herein 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. In general, 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.

[0312] The term “pharmaceutically acceptable basic addition salt” as used herein 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.

[0313] Many of the compounds useful in the methods and compositions of this disclosure have at least one 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.

[0314] Furthermore, certain compounds which contain alkenyl groups may exist as Z (zusammen) or E (entgegen) isomers. In each instance, the disclosure includes both mixture and separate individual isomers.

[0315] Some of the compounds may also exist in tautomeric forms. Such forms, although not explicitly indicated in the formulae described herein, are intended to be included within the scope of the present disclosure. “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.

[0316] The term “Log of solubility”, “LogS” or “logS” as used herein 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.

[0317] EXAMPLES

[0318] The invention now being generally described, it will be more readily understood by reference to the following examples which are included merely for purposes of illustration of certain aspects and embodiments of the present invention, and are not intended to limit the invention.

[0319] Example 1: In vivo effect of MPC inhibition

[0320] Our published data show that topical inhibition of pyruvate oxidation can re-activate HFSCs in aged epidermis. To study aging and the effect of UK5099 under normal conditions, mice at roughly 90 weeks of age were acquired and housed in standard conditions with murine chow formulated with UK5099. Mice were then monitored weekly by photography and a frailty index was calculated to measure aging without disturbing the animals. 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. UK5099 does appear to moderately alter the frailty index overall after 3-4 months of treatment (Figure 2), but several interesting phenotypes emerged. First, tumors developed spontaneously in all of the control mice (out of 26 mice), whereas fewer of the UK5099 treated mice have developed them (out of 20 mice particularly in the liver, where small molecules tend to accumulate (Explored in more detail in project 2 below). Second, many of the control mice developed ‘body condition’ scores which reflects diminished muscle tone in the torso, while this has not yet occurred in any of the UK5099 treated mice (out of 20 mice). Third, we confirmed that systemic administration of UK5099 has a positive effect on the hair cycle in these aged mice. Fourth, we developed a senescence assay using whole tissue that demonstrated a clear effect in aged animals, and a strong effect of MPC inhibition.

[0321] We treat the mice from our colony that are at least 80 weeks of age with these MPC inhibitors and compare to vehicle treated animals. Our published data on 2 year old mice has already shown that stimulation of metabolism and activation of HFSCs can be achieved through topical pharmacological inhibition or genetic blockage of pyruvate oxidation. Our data suggest that systemic inhibition of pyruvate oxidation also promotes activation of HFSCs (Fig 3), which not only demonstrates that UK5099 can be stably delivered via IP injection, but also opens the possibility that other tissue stem cells could also be rejuvenated as well. Recent experiments have determined that metabolic manipulation systemically can achieve the same effect on a broad array of tissues and improve health-span by monitoring a variety of visible signs of aging over the course of the experiment as described in Figure 2 (morbidity, and frailty index).

[0322] The most intriguing finding from our aging experiments is that inhibition of pyruvate oxidation appears to have a potent anti-cancer effect systemically. Because aging is the top risk factor in cancer, it is not surprising that all the control mice developed tumors. On the other hand, the rate of tumorigenesis in UK5099 treated mice was dramatically lower in three independent experiments (one with IP injection, two with drug delivery in chow). Our results stand out because we allowed for tumorigenesis to develop spontaneously in an unbiased fashion, and MPC inhibition clearly had an anti-cancer effect. In fact, these results are consistent with unpublished results from our group showing that genetic deletion of Mpcl in mice led to a lower incidence of melanoma in a GEMM model mouse line. Together, these data suggest that Mpcl inhibition could be an effective anti-cancer strategy more broadly. In figure 7, we show evidence that genetic deletion of MPC1 in melanocyte stem cells is sufficient to diminish tumor formation and invasion in a genetically engineered mouse model (GEMM). Here we will build on our preliminary data suggesting that pharmacological inhibition of MPC1 can inhibit tumorigenesis during aging to determine whether MPC inhibition can have the same effect on melanoma in adult mice. We will again use the GEMM model for melanoma and feed animals control chow or chow formulated with UK5099. It is important to test MPC inhibition pharmacologically to determine if this could be a potentially clinically beneficial approach either alone or in combination with chemotherapy or other metabolic regulatory molecules. Therefore, we derived cell lines from the wild type and Mpcl-KO tumors described in Figure 7. In fact, the Mpcl-KO cell lines grew more slowly than wildtype (Figure 8). Finally, we also found that wild type melanoma cells grown in vitro slow their proliferation when treated with UK5099 (Figure 8).

[0323] 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.

[0324] Measuring survival, it was found that while UK5099 did not extend overall lifespan, more animals survived to a later age, suggesting improved health span (Figure 11).

[0325] Importantly, the UK5099 chow did not affect the overall weight of the animals indicating a lack of toxicity (Figure 12).

[0326] One of the strongest drivers of the change in frailty index was the effect of UK5099 on hair growth. Topical MPC inhibition by UK5099 has been shown previously to promote hair follicle stem cell activation and drive hair growth in young animals, but it was found that systemic administration of UK5099 in aged animals can potentially have the same effect. Shaving the animals upon initiation of UK5099 chow accelerated the hair cycle in aged mice over the course of 1-3 months (Fig 2). Another hallmark of aging in the skin is the thinning of the epidermal and dermal layers. Animals on the UK5099 chow in fact showed an increase in the thickness of both layers, nearly back to the level of young mice (Fig 2).

[0327] Because UK5099 prevented accumulation of lipid deposits in the liver, we next assessed visceral adipogenesis (Figure 15). Isolating fat pads highlighted an accumulation of lipid as judged by increase adipocyte volume in aged mice. This was reversed in aged mice treated with UK5099 (Fig 4).

[0328] The fact that liver tumors were diminished in aged mice treated with UK5099 could signal a change in liver physiology. In fact, 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. Here we found that aged mice showed strong signs of steathosis, or fatty liver disease (FLD) (Fig 4). Mice fed the UK5099 chow on the other hand, showed significantly improved liver morphology, with significantly fewer fatty deposits (Fig 4).

[0329] 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.

[0330] 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.

[0331] Animals treated with UK5099 in their chow showed generally decreased rates of 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 (Figure 22). Aging is one of the strongest risk factors for cancer, therefore we also assessed tumor burden in these animals. Nearly all animals show evidence of some tumorigenesis by the end of their lives in liver, skin, etc. Two batches of aged animals were harvested at one time before natural death and quantified tumorigenesis. Those mice fed UK5099 chow showed a lower tumor burden than those on control chow, particularly in the liver (Fig 1).

[0332] 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 23). Aging is one of the strongest risk factors for cancer, therefore we also assessed tumor burden in these animals. Nearly all animals show evidence of some tumorigenesis by the end of their lives in liver, skin, etc. Two batches of aged animals were harvested at one time before natural death and quantified tumorigenesis. Those mice fed UK5099 chow showed a lower tumor burden than those on control chow, particularly in the liver (Fig 1).

[0333] INCORPORATION BY REFERENCE

[0334] All publications and patents mentioned herein are hereby incorporated by reference in their entirety as if each individual publication or patent was specifically and individually indicated to be incorporated by reference. In case of conflict, the present application, including any definitions herein, will control.

[0335] EQUIVALENTS

[0336] While specific embodiments of the subject invention have been discussed, the above specification is illustrative and not restrictive. Many variations of the invention will become apparent to those skilled in the art upon review of this specification and the claims below. The full scope of the invention should be determined by reference to the claims, along with their full scope of equivalents, and the specification, along with such variations.

Claims

We claim:

1. 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.

2. The method of claim 1, wherein 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.

3. The method of claim 1 or 2, wherein the method comprises systemically inhibiting a mitochondrial pyruvate carrier (MPC) protein.

4. The method of claim 1 or 2, wherein the method comprises inducing adult stem cell activation in an aged tissue.

5. The method of claim 1 or 2, wherein the method comprises reducing at least one sign of aging.

6. The method of claim 1 or 2, wherein the method comprises promoting hair growth.

7. The method of claim 1 or 2, wherein the method comprises inhibiting age-induced tumorigenesis.

8. The method of claim 1, wherein the method comprises treating fatty liver disease.

9. The method of claim 1, wherein the method comprises treating or slowing muscle wastage.

10. The method of any one of claims 1-9, wherein the MPC inhibitor is a compound of formula I or II,wherein: each A is independently CH, CR4, or N;OR10- -P — OR10Y is carboxyl, ester, amide, or O ;Z is CH, CR4, or N.R2is CN or carboxyl;R3is H, aryl, aralkyl, or aralkylacyl, and is optionally substituted by one or more R5, wherein each R5is independently selected from alkyl, alkoxy, or halo; each instance of R4is independently alkyl, carboxyl, halo, hydroxy, ester, or CN;R7is hydrogen, alkyl, halo, hydroxyl, alkoxy, or acyloxy;R10is hydrogen or alkyl; and n is 0-4; or a pharmaceutically acceptable salt thereof.

11. The method of claim 10, wherein Z is CH or N.

12. The method of claim 10, wherein the MPC inhibitor is a compound of formula III,wherein,OR10- -P — OR10MlY is carboxyl, ester, amide, or O ;R2is CN or carboxyl;R3is H, aryl, aralkyl, or aralkylacyl, and is optionally substituted by one or more R5, wherein each R5is independently selected from alkyl, alkoxy, or halo; each instance of R4is independently alkyl, carboxyl, halo, hydroxy, ester, or CN;R6is from H, alkyl, or cycloalkyl; andR7is hydrogen, alkyl, halo, hydroxyl, alkoxy, or acyloxy;R10is hydrogen or alkylR11is H or alkyl; and n is 0-4; or a pharmaceutically acceptable salt thereof.OR10- -P — OR10l13. The method of any one of claims 10-12, wherein Y is °14. The method of claim 13, wherein R10is H.

15. The method of claim 13, wherein R10is alkyl (e.g., ethyl).

16. The method of any one of claims 10-12, wherein Y is ester or amide.

17. The method of any one of claims 12-16, wherein R11is alkyl (e.g., methyl).

18. The method of claim 10, wherein the MPC inhibitor is a compound of formula V, VI, or VII,wherein:each A is independently CH, CR4, or N;X is NR6or O;R1is H or lower alkyl; or either R1and R6or R1and R2, together with the atoms that separate them, complete a heterocycle;R2is CN or carboxyl;R3is H, aryl, aralkyl, or aralkylacyl, and is optionally substituted by one or more R5, wherein each R5is independently selected from alkyl, alkoxy, or halo; each instance of R4is independently alkyl, carboxyl, halo, hydroxy, or CN;R6is from H, alkyl, or cycloalkyl;R7is hydrogen, alkyl, halo, hydroxyl, alkoxy, or acyloxy; and n is 0-4; or a pharmaceutically acceptable salt thereof.

19. The method of any one of claims 10-18, wherein at least one A is N.

20. The method of any one of claims 10-18, wherein exactly one A is N.

21. The method of any one of claims 10-20, wherein the MPC inhibitor is a compound of formula Va, Via, or Vila:wherein:X is NR6or O;R1is H or lower alkyl;R2is CN or carboxyl; or R1and R2, together with the atoms that separate them, complete a heterocycle;R3is H, phenyl, or benzyl, and is optionally substituted by one or more R5, wherein each R5is independently selected from alkyl, alkoxy, or halo; each instance of R4is independently selected from alkyl, carboxyl, halo, hydroxy, or CN;R6is selected from H, alkyl, or cycloalkyl; and n is 0-4;or a pharmaceutically acceptable salt thereof.

22. The method of any one of claims 17-21, wherein X is NH.

23. The method of any one of claims 17-21, wherein X is O.

24. The method of any one of claims 18-21, wherein R1is H.

25. The method of any one of claims 18-21, wherein R1is lower alkyl.

26. The method of any one of claims 18-22, wherein R1and R6, together with the atoms that separate them, complete a heterocycle (e.g., morpholinyl).

27. The method of any one of claims 18-22, wherein R6is hydrogen.

28. The method of any one of claims 18-27, wherein R2is CN.

29. The method of any one of claims 18-27, wherein R2is carboxyl.

30. The method of any one of claims 17-21, wherein R1and R2, together with the atoms that separate them, complete a heterocyclyl selected from thiazolidine-2,4-dion-5-ylidene or 2-iminothiazolidin-4-one- 5 -y lidene .

31. The method of any one of claims 21-30, wherein the compound is of formula Va.

32. The method of any one of claims 21-30, wherein the compound is of formula Via.

33. The method of any one of claims 10-32, wherein R3is H.

34. The method of any one of claims 10-32, wherein R3is phenyl.

35. The method of any one of claims 10-32, wherein R3is phenyl and is substituted by one or more R5.

36. The method of claim 35, wherein R3is substituted by one R5, and wherein R5is an alkoxy.

37. The method of claim 35 or 36, wherein R3is aralkyl (e.g., benzyl or phenethyl).

38. The method of claim 35 or 36, wherein R3is aralkyl.

39. The method of claim 35 or 36, wherein R3is aralkylacyl (e.g., phenylacetyl).

40. The method of claim 35 or 36, wherein R3is benzyl.

41. The method of claim 35 or 36, wherein R3is benzyl and is substituted by one or moreR5.

42. The method of claim 35 or 36, wherein R3is aralkyl (e.g., benzyl or phenethyl) and is substituted by one or more R5(preferably on the phenyl ring).

43. The method of claim 35 or 36, wherein R3is aralkylacyl (e.g., phenylacetyl), and is substituted by one or more R5(preferably on the phenyl ring).

44. The method of any one of claims 41-42, wherein R3is substituted by one or two R5, and wherein each R5is independently selected from fluoroalkyl or fluoro.

45. The method of claim 44, wherein R3is substituted by two R5, and wherein each R5is independently selected from fluoroalkyl or fluoro.

46. The method of claim 44, wherein R3is substituted by two R5, and wherein each R5is trifluoromethyl.

47. The method of claim 46, wherein R3is substituted by two R5in the meta positions, and wherein each R5is trifluoromethyl.

48. The method of any one of claims 18-47, wherein the MPC inhibitor is a compound of formula Vb:

49. The method of any one of claims 21-48, wherein n is 0.

50. The method of claim 49, wherein the MPC inhibitor is a compound of formula Vc:

51. The method of any one of claims 21-48, wherein n is 1.

52. The method of claim 51, wherein the MPC inhibitor is a compound of formula Vd:

53. The method of claim 51, wherein the MPC inhibitor is a compound of formula Ve:

54. The method of any one of claims 51-53, wherein R4is selected from halo or haloalkyl.

55. The method of claim 54, wherein R4is halo (e.g., chloro or bromo).

56. The method of any one of claims 18-30, wherein the MPC inhibitor is a compound of formula VI.

57. The method of any one of claims 18-30, wherein the MPC inhibitor is a compound of formula Via.

58. The method of claim 56 or 57, wherein n is 0.

59. The method of claim 56 or 57, wherein n is 2, and R4is selected from halo or haloalkyl.

60. The method of any one of claims 18-30, wherein the MPC inhibitor is a compound of formula VII.

61. The method of any one of claims 18-30, wherein the MPC inhibitor is a compound of formula Vila.

62. The method of any one of claims 10-61, wherein R7is hydrogen, hydroxyl, halo (e.g., chloro), or acyloxy (e.g., acetyloxy).

63. The method of claim 62, wherein R7is hydroxyl, halo (e.g., chloro), or acyloxy (e.g., acetyloxy).

4. The method of any one of claims 1-9, wherein the MPC inhibitor is selected fromJXL032 JXL033 JXL034 JXL035or a pharmaceutically acceptable salt thereof.

65. The method of any one of claims 1-9, wherein the MPC inhibitor is a compound of formula I, or a pharmaceutically acceptable salt thereof,wherein:OR10- -P — OR10MlY is carboxyl, ester, amide, or ° ;R1is H, aryl, aralkyl, or aralkylacyl, and is optionally substituted by one or more R5;R2is CN or carboxyl;R4is independently alkyl, alkenyl, alkynyl, azido, halo, hydroxy, carboxyl, ester, or CN;R5is independently selected from alkyl, alkoxy, or halo; and n is 0-4.OR10- -P — OR10l66. The method of claim 65, wherein Y is °67. The method of claim 66, wherein R10is H.

68. The method of claim 65 or 66, wherein R10is alkyl (e.g., ethyl).

69. The method of any one of claims 65-68, wherein Y is ester or carboxyl.

70. The method of any one of claims 65-69, wherein R2is CN.

71. The method of any one of claims 65-69, wherein R2is carboxyl.

72. The method of any one of claims 65-71, wherein R1is H.

73. The method of any one of claims 65-71, wherein R1is aralkyl (e.g., benzyl or phenethyl).

74. The method of any one of claims 65-71, wherein R1is aralkyl (e.g., benzyl or phenethyl) and is substituted by one or more R5(preferably on the phenyl ring).

75. The method of any one of claims 65-71, wherein R1is aralkylacyl (e.g., phenylacetyl), and is substituted by one or more R5(preferably on the phenyl ring).

76. The method of any one of claims 73-75, wherein R1is substituted by one or two R5, and wherein each R5is independently selected from fluoroalkyl or fluoro.

77. The method of any one of claims 73-76, wherein R1is substituted by two R5, and wherein each R5is trifluoromethyl.

78. The method of any one of claims 65-77, wherein R4is 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).

79. The method of any one of claims 65-78, wherein R4is not chloro or bromo.

80. The method of any one of claims 65-79, wherein the MPC inhibitor is a compound of formula la:wherein R6is H, alkyl, aryl, or aralkyl,81. The method of any one of claims 1-9, wherein the MPC inhibitor is selected from:pharmaceutically acceptable salt thereof.

82. The method of any one of claims 1 to 81, wherein the at least one sign of aging comprises morbidity, slowed hair cycle, hair graying, ocular occlusion, mobility, kyphosis, cognitive impairment, or any combination thereof.

83. The method of any one of claims 1 to 82, where the patient has baldness or alopecia.

84. The method of any one of claims 1 to 82, wherein 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.

85. The method of any one of claims 1 to 82, wherein the age-induced tumorigenesis is tumorigenesis in skin, liver, kidney, fat, or a combination thereof.

86. The method of claim 85, wherein the tumorigenesis in skin is melanoma.

87. The method of any one of claims 1 to 86, wherein the MPC inhibitor is administered orally.

88. The method of any one of claims 1 to 87, wherein the MPC inhibitor is administered intravenously.

89. The method of any one of claims 1 to 87, wherein the MPC inhibitor is administered parenterally.

90. The method of any one of claims 1-89, wherein the MPC inhibitor is administered for at least about a week.

91. The method of any one of claims 1-89, wherein the MPC inhibitor is administered for at least about a month.

92. The method of any one of claims 1-89, wherein the MPC inhibitor is administered for at least about two months.

93. The method of any one of claims 1-89, wherein the MPC inhibitor is administered for at least about six months.

94. The method of any one of claims 1-89, wherein the MPC inhibitor is administered for at least about a year.

95. The method of any one of claims 1-89, wherein the MPC inhibitor is administered for at least about two years.

96. The method of any one of claims 1-95, wherein the MPC inhibitor is administered daily.

97. The method of any one of claims 1-96, wherein 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.

98. The method of any one of claims 1-96, wherein 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.

99. The method of claim 98, wherein, 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.

100. The method of claim 98, wherein, 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 5% relative to the ratio prior to the systemic administration of the MPC inhibitor.

101. The method of claim 98, wherein, 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.

102. The method of claim 98, wherein, 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.

103. The method of claim 98, wherein, 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 5% relative to the ratio prior to the systemic administration of the MPC inhibitor.

104. The method of claim 98, wherein, 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.

105. The method of claim 98, wherein, 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.

106. The method of claim 98, wherein 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 10% relative to the ratio prior to the systemic administration of the MPC inhibitor.

107. The method of claim 98, wherein, 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.

108. The method of claim 98, wherein, 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.

109. The method of claim 98, wherein, 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 10% relative to the ratio prior to the systemic administration of the MPC inhibitor.

110. The method of claim 98, wherein, 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.

111. The method of claim 98, wherein, 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.

112. The method of claim 98, wherein, 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.

113. The method of claim 98, wherein, 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 50% relative to the ratio prior to the systemic administration of the MPC inhibitor.

114. The method of claim 98, wherein, 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.

115. The method of claim 98, wherein, 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.

116. The method of claim 98, wherein, 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 50% relative to the ratio prior to the systemic administration of the MPC inhibitor.

117. The method of claim 98, wherein, 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.

118. The method of claim 98, wherein, 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.

119. The method of claim 98, wherein, 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.

120. The method of claim 98, wherein, 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 100% relative to the ratio prior to the systemic administration of the MPC inhibitor.

121. The method of claim 98, wherein, 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.

122. The method of claim 98, wherein, 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.

123. The method of claim 98, wherein, 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 100% relative to the ratio prior to the systemic administration of the MPC inhibitor.

124. The method of claim 98, wherein, 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.

125. The method of claim 98, wherein, 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.

126. The method of claim 98, wherein, 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.

127. The method of any one of claims 1-126, wherein, following the systemic administration of the MPC inhibitor, the MPC inhibitor is essentially not detectable in skin.

128. The method of any one of claims 1-126, wherein, following the systemic administration of the MPC inhibitor, the MPC inhibitor is not detectable in skin.

129. The method of claim 127 or 128, wherein the MPC inhibitor is detected via mass spectrometry.

130. The method of claim 129, wherein the MPC detection method is liquid chromatography-mass spectrometry.

131. 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, CR4, or N;OR10- -P — OR10Y is carboxyl, ester, amide, or O ;Z is CH, CR4, or N.R2is CN or carboxyl;R3is aralkyl or aralkylacyl, wherein R3is substituted by two R5in the meta positions, wherein each R5is independently selected from alkyl, alkoxy, or halo; each R4is independently alkyl, carboxyl, halo, hydroxy, ester, or CN;R7is hydrogen, alkyl, halo, hydroxyl, alkoxy, or acyloxy;R10is hydrogen or alkyl; and n is 0-4; or a pharmaceutically acceptable salt thereof.

132. The nutritional supplement of claim 131, wherein Z is CH or N.

133. The nutritional supplement of claim 131, wherein the MPC inhibitor is a compound of formula III,wherein,OR10- -P — OR10MlY is carboxyl, ester, amide, or ° ;R2is CN or carboxyl;R3is aralkyl or aralkylacyl, wherein R3is substituted by two R5in the meta positions, wherein each R5is independently selected from alkyl, alkoxy, or halo; each R4is independently alkyl, carboxyl, halo, hydroxy, ester, or CN;R7is hydrogen, alkyl, halo, hydroxyl, alkoxy, or acyloxy; andR10is hydrogen or alkyl; or a pharmaceutically acceptable salt thereof.OR10- -P — OR10Ml134. The nutritional supplement of any one of claims 131-133, wherein Y is 0135. The nutritional supplement of claim 134, wherein R10is H.

136. The nutritional supplement of claim 134, wherein R10is alkyl (e.g., ethyl).

137. The nutritional supplement of any one of claims 131-1133, wherein Y is ester or amide.

138. The nutritional supplement of claim 131, wherein the MPC inhibitor is a compound of formula V, VI, or VII,wherein: each A is independently CH, CR4, or N;X is NR6or O;R1is H or lower alkyl; or either R1and R6or R1and R2, together with the atoms that separate them, complete a heterocycle;R2is CN or carboxyl;R3is aralkyl or aralkylacyl, wherein R3is substituted by two R5in the meta positions, wherein each R5is independently selected from alkyl, alkoxy, or halo; each R4is independently alkyl, carboxyl, halo, hydroxy, or CN;R6is from H, alkyl, or cycloalkyl;R7is hydrogen, alkyl, halo, hydroxyl, alkoxy, or acyloxy; and n is 0-4; or a pharmaceutically acceptable salt thereof.

139. The nutritional supplement of any one of claims 131-138, wherein at least one A is N.

140. The nutritional supplement of any one of claims 131-138, wherein exactly one A is N.

141. The nutritional supplement of any one of claims 131-140, wherein the MPC inhibitor is a compound of formula Va, Via, or Vila:wherein:X is NR6or O;R1is H or lower alkyl;R2is CN or carboxyl; or R1and R2, together with the atoms that separate them, complete a heterocycle;R3is benzyl, wherein R3is substituted by two R5in the meta positions, wherein each R5is independently selected from alkyl, alkoxy, or halo; each R4is independently selected from alkyl, carboxyl, halo, hydroxy, or CN;R6is selected from H, alkyl, or cycloalkyl; and n is 0-4; or a pharmaceutically acceptable salt thereof.

142. The nutritional supplement of any one of claims 138-141, wherein X is NH.

143. The nutritional supplement of any one of claims 138-141, wherein X is O.

144. The nutritional supplement of any one of claims 138-141, wherein R1is H.

145. The nutritional supplement of any one of claims 138-141, wherein R1is lower alkyl.

146. The nutritional supplement of any one of claims 138-42, wherein R1and R6, together with the atoms that separate them, complete a heterocycle (e.g., morpholinyl).

147. The nutritional supplement of any one of claims 138-142, wherein R6is hydrogen.

148. The nutritional supplement of any one of claims 138-147, wherein R2is CN.

149. The nutritional supplement of any one of claims 138-147, wherein R2is carboxyl.

150. The nutritional supplement of any one of claims 138-141, wherein R1and R2, 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.

151. The nutritional supplement of any one of claims 141-150, wherein the MPC inhibitor is a compound of formula Va.

152. The nutritional supplement of any one of claims 141-150, wherein the MPC inhibitor is a compound of formula Via.

153. The nutritional supplement of any one of claims 141-152, wherein R3is aralkyl (e.g., benzyl or phenethyl).

154. The nutritional supplement of any one of claims 141-152, wherein R3is aralkylacyl (e.g., phenylacetyl).

155. The nutritional supplement of claim 153, wherein R3is benzyl.

156. The nutritional supplement of any one of claims 131-155, wherein each R5is independently selected from fluoroalkyl or fluoro.

157. The nutritional supplement of claim 156, wherein each R5is trifluoromethyl.

158. The nutritional supplement of any one of claims 138-140, wherein the MPC inhibitor is a compound of formula Vb:

159. The nutritional supplement of claim 158, wherein n is 0.

160. The nutritional supplement of claim 158, wherein n is 1.

161. The nutritional supplement of any one of claims 138-140, wherein the MPC inhibitor is a compound of formula Vd:

162. The nutritional supplement of claim 141-157, wherein the MPC inhibitor is a compound of formula Ve:

163. The nutritional supplement of any one of claims 160-162, wherein R4is selected from halo or haloalkyl.

164. The nutritional supplement of claim 163, wherein R4is halo (e.g., chloro or bromo).

165. The nutritional supplement of any one of claims 138-150, wherein the MPC inhibitor is a compound of formula VI.

166. The nutritional supplement of any one of claims 141-150, wherein the MPC inhibitor is a compound of formula Via.

167. The nutritional supplement of claim 165 or 166, wherein n is 0.

168. The nutritional supplement of claim 165 or 166, wherein n is 2, and R4is selected from halo or haloalkyl.

169. The nutritional supplement of any one of claims 138-150, wherein the MPC inhibitor is a compound of formula VII.

170. The nutritional supplement of any one of claims 141-150, wherein the MPC inhibitor is a compound of formula Vila.

171. The nutritional supplement of any one of claims 131-140, wherein R7is hydrogen, hydroxyl, halo (e.g., chloro), or acyloxy (e.g., acetyloxy).

172. The nutritional supplement of claim 170, wherein R7is hydroxyl, halo (e.g., chloro), or acyloxy (e.g., acetyloxy).

173. The nutritional supplement of claim 131, wherein the MPC inhibitor is selected fromor a pharmaceutically acceptable salt thereof.

174. The nutritional supplement of claim 131, wherein the MPC inhibitor is a compound of formula I, or a pharmaceutically acceptable salt thereof,wherein:OR10- -P — OR10lY is carboxyl, ester, amide, or 0 ;R1is aralkyl or aralkylacyl, wherein R3is substituted by two R5in the meta positions;R2is CN or carboxyl;R4is independently alkyl, alkenyl, alkynyl, azido, halo, hydroxy, carboxyl, ester, or CN; andR5is independently selected from alkyl, alkoxy, or halo.OR10- -P — OR10Ml175. The nutritional supplement of claim 174 wherein Y is 0176. The nutritional supplement of any one of claims 174 or 175, wherein R10is H.

177. The nutritional supplement of any claim 175 or 176, wherein R10is alkyl (e.g., ethyl).

178. The nutritional supplement of claim 174, wherein Y is ester or carboxyl.

179. The nutritional supplement of any one of claims 174-178, wherein R2is CN.

180. The nutritional supplement of any one of claims 174-178, wherein R2is carboxyl.

181. The nutritional supplement of any one of claims 174-180, wherein R1is aralkyl (e.g., benzyl or phenethyl).

182. The nutritional supplement of any one of claims 174-180, wherein R1is aralkylacyl (e.g., phenylacetyl).

183. The nutritional supplement of claim 181 or 182, wherein each R5is independently selected from fluoroalkyl or fluoro.

184. The nutritional supplement of any one of claims 181-183, wherein each R5is trifluoromethyl.

185. The nutritional supplement of any one of claims 174-184, wherein R4is 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).

186. The nutritional supplement of any one of claims 174-185, wherein R4is not chloro or bromo.

187. The nutritional supplement of any one of claims 174-186, wherein the MPC inhibitor is a compound of formula la:wherein R6is H, alkyl, aryl, or aralkyl.

188. The nutritional supplement of claim 131, wherein the MPC inhibitor is selected from:pharmaceutically acceptable salt thereof.

189. The nutritional supplement of any one of claims 131-188, wherein the nutritional supplement further comprises a multivitamin complex.

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