Compositions for treating obesity and insulin resistance disorders

• US 8,846,724 B2
• Filed: 07/27/2011
• Issued: 09/30/2014
• Est. Priority Date: 12/29/2003
• Status: Expired due to Fees

• Current Assignee: President and Fellows of Harvard College (Harvard Corporation), The General Hospital Corporation (Mass General Brigham, Inc.)
• Original Assignee: President and Fellows of Harvard College (Harvard Corporation), The General Hospital Corporation (Mass General Brigham, Inc.)
• Inventors: Sinclair, David A., Alexander-Bridges, Maria
• Primary Examiner(s): Weddington, Kevin E
• Application Number:
  US13/192,011
• Publication Number:
  US 20120029065A1
• Time in Patent Office: 1,161 Days
• Field of Search: 514/356, 514/456, 514/635, 514/866, 514/909
• US Class Current: 514/356
• CPC Class Codes: A61K 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61K 31/05 Phenols cannabinoids A61K31/658
• CPC Class Codes: A61K 31/12 Ketones
• CPC Class Codes: A61K 31/353 3,4-Dihydrobenzopyrans, e.g. chroman, catechin
• CPC Class Codes: A61K 31/455 Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
• CPC Class Codes: A61K 31/7048 having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin , digitoxin or digoxin
• CPC Class Codes: A61K 31/7052 having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
• CPC Class Codes: A61K 31/706 containing six-membered rings with nitrogen as a ring hetero atom
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 1/14 Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/50 for increasing or potentiating the activity of insulin

Abstract

Provided herein are methods and compositions for modulating the activity or level of a sirtuin, thereby treating or preventing obesity or an insulin resistance disorder, such as diabetes in a subject. Exemplary methods comprise contacting a cell with a sirtuin activating compound or an inhibitory compound to thereby increase or decrease fat accumulation, respectively.

Claims

1. A method of treating an insulin resistance disorder in a subject in need thereof, comprising administering to a subject in need thereof a therapeutically effective amount of a sirtuin-activating compound, or salt thereof, wherein the sirtuin-activating compound, or salt thereof, has at least about 2-fold less antioxidant activity than resveratrol, and wherein the sirtuin-activating compound, or salt thereof, is not a compound selected from the group consisting of a flavone, myricetin, quercetin, fisetin, kaempferol, a catechin, nordihydroguaiaretic acid (NDGA) and caffeic acid phenethyl ester.

2. The method of claim 1, wherein the sirtuin-activating compound, or salt thereof is a non-naturally occurring compound.

3. The method of claim 1, further comprising administering to the subject a second agent that:

(i) increases the activity or protein level of a sirtuin in a cell;

increases the activity or protein level of 5′

-AMP-activated protein kinase (AMPK) in a cell;

or is an anti-diabetic agent.

4. The method of claim 3, wherein the second agent is an anti-diabetic agent.

5. The method of claim 1, wherein the insulin resistance disorder is diabetes.

6. The method of claim 1, wherein the insulin resistance disorder is obesity.

7. The method of claim 1, wherein the insulin resistance disorder is metabolic syndrome.

8. The method of claim 2, wherein the non-naturally occurring compound activates the deacetylase activity of SIRT1 by a factor of at least about 5.

9. The method of claim 8, wherein the non-naturally occurring compound activates the deacetylase activity of SIRT1 by a factor of at least about 10.

10. The method of claim 9, wherein the non-naturally occurring compound activates the deacetylase activity of SIRT1 by a factor of at least about 20.

11. The method of claim 2, wherein the non-naturally occurring compound has an EC₅₀ for activating SIRT1 that is less than about 100 μ

M.

12. The method of claim 11, wherein the non-naturally occurring compound has an EC₅₀ for activating SIRT1 that is less than about 10 μ

M.

13. The method of claim 12, wherein the non-naturally occurring compound has an EC₅₀ for activating SIRT1 that is less than about 1 μ

M.

14. The method of claim 2, wherein the non-naturally occurring compound does not substantially inhibit the catalytic activity of cyclooxygenase.

15. The method of claim 2, wherein the non-naturally occurring compound does not substantially inhibit PI3-kinase.

16. The method of claim 2, wherein the non-naturally occurring compound does not substantially inhibit tyrosine protein kinase.

17. The method of claim 3, wherein the second agent is an anti-obesity agent.

18. The method of claim 1 for the treatment of a human subject.

19. The method of claim 1, wherein the sirtuin-activating compound has at least about 3-fold less antioxidant activity than resveratrol.

20. The method of claim 1, wherein the sirtuin-activating compound has at least about 5-fold less antioxidant activity than resveratrol.

21. The method of claim 1, wherein the sirtuin-activating compound has at least about 10-fold less antioxidant activity than resveratrol.