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(12) United States Patent (10) Patent No.: US 9,463,173 B2 Bumpus Et Al

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(12) United States Patent (10) Patent No.: US 9,463,173 B2 Bumpus Et Al USOO94631 73B2 (12) United States Patent (10) Patent No.: US 9,463,173 B2 Bumpus et al. (45) Date of Patent: Oct. 11, 2016 (54) COMPOSITIONS AND METHODS FOR OTHER PUBLICATIONS TREATING OBESITY AND OBESTY-RELATED CONDITIONS Ghodke-Puranik, et. al., “Valproic acid pathway: pharmacokinetics and pharmacodynamics' Pharmacogenetics and genomics (2013). (71) Applicant: THE JOHNS HOPKINS Silva, M., et al., “Differential effect of valproate and its Delta2- and Delta4-unsaturated metabolites, on the beta-Oxidation rate of long UNIVERSITY, Baltimore, MD (US) chain and medium-chain fatty acids' Chem Biol Interact. (Sep. 28. 2001) vol. 137, No. 3, pp. 203-212. (72) Inventors: Namandje Bumpus, Washington, DC Zhang, L, et al., “Combined effects of a high-fat diet and chronic (US); Lindsay Avery, S. Hamilton, MA valproic acid treatment on hepatic Steatosis and hepatotoxicity in (US) rats'. Acta Pharmacol Sin. (Mar. 2014) vol. 35. No. 3, pp. 363-372. Meral, C., et al., “New adipocytokines (vaspin, apelin, visfatin, (73) Assignee: THE JOHNS HOPKINS adiponectin) levels in children treated with valproic acid” Eur UNIVERSITY, Baltimore, MD (US) Cytokine Netw. (Jun. 2011) vol. 22, No. 2, pp. 118-122. Acheampong, A., et al., “Identification of valproic acid metabolites *) Notice: Subject to anyy disclaimer, the term of this in human serum and urine using hexadeuterated valproic acid and patent is extended or adjusted under 35 gas chromatographic mass spectrometric analysis'. Biomed Mass U.S.C. 154(b) by 0 days. Spectrom (1983) vol. 10, No. 11, pp. 586-595. Becker, C., et al., “Influence of valproic acid on hepatic carbohy drate and lipid metabolism”, Arch Biochem Biophys (1983) vol. (21) Appl. No.: 14/637,784 223, No. 2, pp. 381-392. Foretz, M., “Metformin inhibits hepatic gluconeogenesis in mice (22) Filed: Mar. 4, 2015 independently of the LKB1/AMPK pathway via a decrease in hepatic energy state” J. Clin Invest (Jul. 2010) vol. 120, No. 7, pp. (65) Prior Publication Data 2355-2369. US 2015/O250747 A1 Sep. 10, 2015 Nau, H., et al., “Valproic acid and metabolites: pharmacological and toxicological studies' Epilepsia (1984) vol. 25 (Suppl. 1), S14-S22. Shaw, R. “The kinase LKB1 mediates glucose homeostasis in liver Related U.S. Application Data and therapeutic effects of metformin', Science, (Dec. 9, 2005) vol. 310, pp. 1642-1646. (60) Provisional application No. 61/947,537, filed on Mar. Silva, M., "Valproic acid metabolism and its effects on 4, 2014. mitochondrial fatty acid oxidation: a review” J Inherit Metab Dis, (2008) vol. 31, pp. 205-216. (51) Int. Cl. Sztajnkrycer, M.. “Valproic acid toxicity: overview and manage AOIN 37/00 (2006.01) ment” J. Toxicol Clin Toxicol, (2002) vol. 40, No. 6, pp. 789-801. A6 IK3I/I9 (2006.01) (52) U.S. Cl. * cited by examiner CPC ..................................... A61K 31/19 (2013.01) Primary Examiner — Jeffrey H Murray (58) Field of Classification Search None (74) Attorney, Agent, or Firm — Johns Hopkins See application file for complete search history. Technology Transfer (57) ABSTRACT (56) References Cited The present invention relates to the field of obesity. More U.S. PATENT DOCUMENTS specifically, the present invention provides methods and compositions useful in treating obesity and obesity-associ 6, 191,117 B1 2, 2001 Kozachuk ated conditions. In one embodiment, a method for treating obesity in a Subject comprises the step of administering an FOREIGN PATENT DOCUMENTS effective amount of valproic acid (VPA) or an analog, WO O2O3915 A2 1, 2002 derivative or metabolite thereof to the subject. WO 2007OO9539 A2 1, 2007 WO 2007O67341 A2 6, 2007 6 Claims, 15 Drawing Sheets U.S. Patent Oct. 11, 2016 Sheet 1 of 15 US 9,463,173 B2 FG. A WPA p-ACC ACC 3-Actin FIG. B U.S. Patent Oct. 11, 2016 Sheet 2 of 15 US 9,463,173 B2 U.S. Patent Oct. 11, 2016 Sheet 3 of 15 US 9,463,173 B2 Compound C - - + + p-ACC p-AMPKa. 3-Actin U.S. Patent Oct. 11, 2016 Sheet 4 of 15 US 9,463,173 B2 (oxidww-du?96ue? & FIG. 2B U.S. Patent Oct. 11, 2016 Sheet 5 Of 15 US 9,463,173 B2 FIG. 2C U.S. Patent Oct. 11, 2016 Sheet 6 of 15 US 9,463,173 B2 A Time hrs) 4. 8 2. WA . p-ACC p-AMPKc, B-Actin FIG. 3A B Time (hrs) 1 4. 8 24 WPA p-ACC p-AMPKa B-Actin FIG. 3B U.S. Patent Oct. 11, 2016 Sheet 7 Of 15 US 9,463,173 B2 Time (hrs) f p-ACC p-AMPKa 3-Actin FIG. 3C Time (hrs) - - - - 8 WPA p-ACC p-AMPKa B-Actin FIG. 3D U.S. Patent Oct. 11, 2016 Sheet 8 of 15 US 9,463,173 B2 A s p-ACC B-Actin p-AMPKo. 3-Actin FIG. 4A U.S. Patent Oct. 11, 2016 Sheet 9 Of 15 US 9,463,173 B2 WPA - - - - AB - - - - P-AM PKC. B-Actin . U.S. Patent Oct. 11, 2016 Sheet 10 of 15 US 9,463,173 B2 A Mouse liver Crude Nuclear Extract U.S. Patent Oct. 11, 2016 Sheet 11 of 15 US 9,463,173 B2 it se : & es : s: FIG 5D U.S. Patent Oct. 11, 2016 Sheet 12 of 15 US 9,463,173 B2 treated yetforfeit Wairoic Acid U.S. Patent US 9,463,173 B2 1. U.S. Patent Oct. 11, 2016 Sheet 14 of 15 US 9,463,173 B2 !!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!! ?ae:º!·?ae ¿ U.S. Patent Oct. 11, 2016 Sheet 15 Of 15 US 9,463,173 B2 Asparate ysiae ethiotite 2880; 23888 $800i : 3888 sai ano; 88 2889 3888 & ai. ai. s .’ isits Phenylaianiae tyrosis : g 8 : 8: s s & : s i . : s s Adecisie w 8: e 800900; 308300; : 83 S.: good;: e 8 8. : 8. : y * s US 9,463,173 B2 1. 2 COMPOSITIONS AND METHODS FOR mouse hepatocytes with VPA resulted in increased levels of TREATING OBESITY AND phosphorylated AMPK and acetyl-CoA carboxylase (ACC). OBESTY-RELATED CONDITIONS This finding was recapitulated using primary human hepato cytes. Pretreatment of mouse hepatocytes with a small CROSS-REFERENCE TO RELATED molecule inhibitor of AMPK, Compound C (6-4-(2-piperi APPLICATIONS din-1-ylethoxy)phenyl-3-pyridin-4-ylpyrazolo 1.5-a pyrimidine), abrogated the phosphorylation of ACC This application claims priority to U.S. Provisional Patent following treatment with VPA. The cytochrome P450 inhibi Application Ser. No. 61/947,537, filed Mar. 4, 2014, which tor 1-aminobenzotriazole blocked the VPA-stimulated phos is incorporated herein by reference in its entirety. 10 phorylation of AMPK, Suggesting a requirement for biotransformation of VPA. In line with this, treatment of STATEMENT OF GOVERNMENTAL INTEREST hepatocytes with metabolites of VPA resulted in increased phosphorylation of AMPK/ACC as compared with VPA. This invention was made with government Support under 15 Treatment of ob/ob mice with VPA for 14 days resulted in grant no. R01 GM103853, awarded by the National Institutes decreased liver masses, hepatic fat accumulation, and serum of Health. The government has certain rights in the inven glucose. These results paralleled those observed in mice tion. treated with metformin. In addition, a targeted mass spec FIELD OF THE INVENTION trometry-based metabolomics assay revealed several Small molecules that were differentially abundant in the serum of The present invention relates to the field of obesity. More ob?ob mice treated with VPA as compared with vehicle specifically, the present invention provides methods and treated mice. These studies are the first to establish VPA and compositions useful in treating obesity and obesity-associ its metabolites as in vitro activators of AMPK. ated conditions. Accordingly, in one aspect, the present invention provides 25 methods for treating obesity and obesity-associated condi BACKGROUND OF THE INVENTION tions. In particular embodiments, a method for reducing hepatic fat accumulation and serum glucose in a subject Obesity has become a global epidemic afflicting both comprising the step of administering an effective amount of children and adults, and gradually spreading from the West valproic acid (VPA) or metabolite thereof to the subject. In ern countries to the developing nations as well. It is now 30 other embodiments, a method for treating obesity in a widely recognized that obesity is associated with, and is Subject comprises the step of administering an effective actually a major culprit in, numerous comorbidities such as amount of valproic acid (VPA) or an analog, derivative or cardiovascular diseases (CVD), type 2 diabetes, hyperten metabolite thereof to the subject. In yet another embodi Sion, certain cancers, and sleep apnea/sleep-disordered ment, a method for treating type 2 diabetes in a subject breathing. As recently acknowledged by a joint American 35 comprises the step of administering an effective amount of Heart Association and American Diabetes Association valproic acid (VPA) or an analog, derivative or metabolite (AHA/ADA) statement, obesity is an independent risk factor thereof to the subject. In certain embodiments, the VPA for CVD, and CVD risks have also been documented in metabolite is one or more of 2-ene-VPA, 4-ene-VPA, 3-OH obese children. Obesity is associated with an increased risk VPA, and 3-keto-VPA. In a specific embodiment, the VPA of overall morbidity and mortality as well as reduced life 40 metabolite is 4-ene VPA. In certain embodiments, the VPA expectancy. Indeed, obesity and overweight are now listed metabolite is administered at a lower dose than the recom as independent cardiovascular risk factors in the joint AHA/ mended VPA dose. ADA call for the prevention of cardiovascular disease and diabetes. BRIEF DESCRIPTION OF THE FIGURES With the exception of bariatric surgery, which can only be 45 offered to a limited number of subjects, the lack of any truly FIG.
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