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Wo 2007/008548 A2 (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (43) International Publication Date PCT (10) International Publication Number 18 January 2007 (18.01.2007) WO 2007/008548 A2 (51) International Patent Classification: Marie [FR/FR]; 16, rue de Austerlitz, F-67000 Strasboug A61K 31/05 (2006.01) A61P 3/04 (2006.01) (FR). DIPP, Michelle [US/US]; 10 Museum Way #1028, (21) International Application Number: Cambridge, MA 02141 (US). PCT/US2006/026272 (74) Agent: VINCENT, Matthew, P.; Fish & Neave IP Group, (22) International Filing Date: 7 July 2006 (07.07.2006) Ropes & Gray LLP, One International Place, Boston, MA 02110-2624 (US). (25) Filing Language: English (81) Designated States (unless otherwise indicated, for every (26) Publication Language: English kind of national protection available): AE, AG, AL, AM, (30) Priority Data: AT,AU, AZ, BA, BB, BG, BR, BW, BY, BZ, CA, CH, CN, 60/697,443 7 July 2005 (07.07.2005) US CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, EG, ES, FI, 60/736,528 14 November 2005 (14.1 1.2005) US GB, GD, GE, GH, GM, HN, HR, HU, ID, IL, IN, IS, JP, 60/753,606 23 December 2005 (23.12.2005) US KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LT, 60/783,802 16 March 2006 (16.03.2006) US LU, LV,LY,MA, MD, MG, MK, MN, MW, MX, MZ, NA, (71) Applicant (for all designated States except US): SIRTRIS NG, NI, NO, NZ, OM, PG, PH, PL, PT, RO, RS, RU, SC, PHARMACEUTICALS, INC. [US/US]; 790 Memorial SD, SE, SG, SK, SL, SM, SY, TJ, TM, TN, TR, TT, TZ, Drive, Suite 104, Cambridge, MA 02139 (US). UA, UG, US, UZ, VC, VN, ZA, ZM, ZW (72) Inventors; and (84) Designated States (unless otherwise indicated, for every (75) Inventors/Applicants (for US only): MILBURN, kind of regional protection available): ARIPO (BW, GH, Michael [US/US]; 508 Hollowridge Court, Cary, NC GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, 27519-9725 (US). MILNE, JUl [US/US]; 169 Mason ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), Terrace, Brookline, MA 02446-2768 (US). AUWERX, European (AT,BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, Johan [BE/FR]; 195, rue de Moulin, F-67150 Hindisheim FR, GB, GR, HU, IE, IS, IT, LT, LU, LV,MC, NL, PL, PT, (FR). ARGMANN, Carmen [CA/FR]; 3, rue del Ia RO, SE, SI, SK, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, Petite Auserlitz, F-67000 Strasbourg (FR). LAGOUGE, GN, GQ, GW, ML, MR, NE, SN, TD, TG). [Continued on next page] (54) Title: METHODS AND RELATED COMPOSITIONS FOR TREATING OR PREVENTING OBESITY, INSULIN RESIS TANCE DISORDERS, AND MITOCHONDRIAL- ASSOCIATED DISORDERS duration of the treatment (in weeks) Body Fat Content (57) Abstract: Provided herein are methods and compositions for treating or preventing metabolic disorders, such as obesity and diabetes. Methods may comprise modulating the activity or level of a sirtuin, such as SIRTl or Sir2. Exemplary methods comprise contacting a cell with a sirtuin activating compound, such as a flavone, stilbene, flavanone, isoflavone, catechin, chalcone, tannin or anthocyanidin, or an inhibitory compound, such as nicotinamide. Published: For two-letter codes and other abbreviations, refer to the "Guid- — without international search report and to be republished ance Notes on Codes and Abbreviations" appearing at the begin- upon receipt of that report ning of each regular issue of the PCT Gazette. METHODS AND RELATED COMPOSITIONS FOR TREATING OR PREVENTING OBESITY, INSULIN RESISTANCE DISORDERS, AND MITOCHONDRIAL-ASSOCIATED DISORDERS Background Obesity is a chronic condition that is characterized by a body mass index (BMI) over 25. Both congenital and environmental factors, such as exercise and eating habits, contribute to the disease. For instance, the hormone Ieptin has been shown to be involved in fat accumulation and regulating eating behavior. Several animal models of obesity result from mutations in the Ieptin and/or Ieptin receptor gene. In addition to affecting the lifestyle of an individual, obesity can lead to a number of complications and diseases, including insulin resistance, Type II diabetes, gallbladder disease, hypertension, cardiovascular disease, hyperlipidemia, sleep apnea, coronary artery disease, knee osteoarthritis, gout, infertility, breast cancer, endometrial cancer, colon cancer and lower back pain. Diabetes is a disease that shows an acute symptom due to a remarkably high blood sugar or ketoacidosis, or as well as chronic, general metabolic abnormalities arising from a prolonged high blood sugar status or a decrease in glucose tolerance. Both congenital and environmental factors, such as exercise and eating habits, contribute to the disease. The pathogenic causes of diabetes are insulin productive disorders, secretion disorders or reductions in activities and sensitivities of the secreted insulin. Diabetes is largely grouped into the following two types: insulin- dependent diabetes mellitus (also known as Type I diabetes) and non-insulin- dependent diabetes mellitus (also known as Type II diabetes). The incidence of Type II diabetes is remarkably increased in obese patients. Treatments for obesity are generally directed to suppressing the appetite of the subject. Whereas a number of appetite suppressants are available (diethylpropion tenuate, mazindol, orlistat, phendimetrazine, phentermine, sibutramine), these compounds may not be effective in all subjects or may be of limited efficacy. Accordingly, new treatments for obesity are needed. A number of treatments for diabetes are well known and include oral hypoglycemic agents such as sulfonylureas that increase insulin secretion (for example, tolbutamide, chlorpropamide and glibenclamide), biguanides (for example, metformin and buformin) that increase glucose uptake and utilization and α- glucosidase inhibitors (for example, acarbose and voglibose). In addition, thiazolidinediones, such as troglitazone, rosiglitazone and pioglitazone, are used to ameliorate insulin-resistance. However, thiazolidinedione intake is usually associated with a weight gain. Thus, there is a still a need for more effective therapies for diabetes. Currently 8% and 15% of adults in the United States are diabetic or obese, respectively. With the number of individuals affected with diabetes, particularly with type II diabetes, and obesity on the increase, there is a dire need for medications that prevent and treat these conditions. Summary In one aspect, the invention provides methods for treating and/or preventing metabolic disorders, such as diabetes and obesity, by administering to a subject a high dose a sirtuin activator. The sirtuin activator may be administered alone or in combination with another iipid-lowering, anti-obesity and/or anti-diabetes agent. When administering a sirtuin activator as a combination with another therapeutic agent, it may be possible to administer a lower dose of the therapeutic agent than is typically required. By using a lower dose of the therapeutic agent, it is possible to reduce or eliminate undesirable side effects, such as, hypertension, elevated heart rate, etc. that may be associated with such agents. In certain embodiments, co¬ administration of a sirtuin activating agent with an anti-diabetic or anti-obesity drug may reduce or eliminate side effects because the activity of the sirtuin activator counteracts or prevents the side effects associated with the therapeutic agent. In other aspects, the invention provides pharmaceutical compositions comprising a high dose of a sirtuin activator in a single dosage form. Such pharmaceutical compositions may be formulated for sustained release over at least about 6 to 48 hours or more. Also provided are neutraceuticals, such as food or beverages, that are supplemented with a sirtuin activator. In another aspect, the invention provides methods for treating or preventing a variety diseases or disorders by administering to a subject a high dose of a sirtuin activating compound. Exemplary diseases and disorders that may be treated with a high dose of a sirtuin activating compound include, for example, diseases or disorders related to aging or stress, diabetes, obesity, neurodegenerative diseases, diseases or disorders associated with mitochondrial dysfunction, chemotherapeutic induced neuropathy, neuropathy associated with an ischemic event, ocular diseases and/or disorders, cardiovascular disease, blood clotting disorders, inflammation, and/or flushing, etc. As described further below, the methods comprise administering to a subject in need thereof a high dose of a sirtuin activating compound. In certain aspects, a high dose of a sirtuin activating compound may be administered alone or in combination with other compounds, including other sirtuin- modulating compounds, or other therapeutic agents. Brief Description of the Drawings Figure 1 shows examples of plant polyphenol sirtuin 1 (SIRTl) activators. Figure 2 shows examples of stilbene and chalcone SIRTl activators. Figure 3 shows examples of flavone SIRTl activators. Figure 4 shows examples of flavone SIRTl modulators Figure 5 shows examples of isoflavone, flavanone and anthocyanidin SIRTl modulators. Figure 6 shows examples of catechin (Flavan-3-ol) SIRTl modulators. Figure 7 shows examples of free radical protective SIRTl modulators. Figure 8 shows examples of SIRTl modulators. Figure 9 shows examples of SIRTl modulators. Figure 10 shows examples of resveratrol analog SIRTl activators. Figure 11 shows further examples of resveratrol analog SIRTl activators. Figure 12 shows further examples of resveratrol analog SIRTl activators. Figure 13 shows examples of resveratrol analog SIRTl modulators. Figure 14 shows further examples of resveratrol analog SIRTl modulators. Figures 15A-G shows examples of sirtuin activators. Figure 16 shows examples of sirtuin inhibitors. Figures 17 A-C are graphs showing that the Sirt-1 activator resveratrol (400 mg/kg/day), co-administered with a high fat diet, prevents diet-induced obesity in male C57BL/6J mice. (A) Food intake of mice expressed as kcal per 24 h. (B) Body weight evolution over time. (C) Comparison of body fat content, as analyzed by dexa scanning, at week 1and week 12 of treatment. Values are represented as the mean ± SEM (n=10).
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