Compositions for treating obesity and insulin resistance disorders

• US 8,017,634 B2
• Filed: 07/01/2005
• Issued: 09/13/2011
• Est. Priority Date: 12/29/2003
• Status: Active Grant

• 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:
  US11/174,000
• Publication Number:
  US 20060111435A1
• Time in Patent Office: 2,265 Days
• Field of Search: 514/356, 514/456, 514/866, 514/635, 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 human in need thereof, comprising administering to the human a therapeutically effective amount of a non-naturally occurring compound that increases the activity and/or protein level of SIRT1.

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

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

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

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

6. 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.

7. The method of claim 6, wherein the non-naturally occurring compound activates the deacetylase activity of SIRT1 by a factor of at least about 10.

8. The method of claim 7, wherein the non-naturally occurring compound activates the deacetylase activity of SIRT1 by a factor of at least about 20.

9. 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.

10. The method of claim 9, wherein the non-naturally occurring compound has an EC₅₀ for activating SIRT1 that is less than about 10 μ

M.

11. The method of claim 10, wherein the non-naturally occurring compound has an EC₅₀ for activating SIRT1 that is less than about 1 μ

M.

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

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;

is an anti-diabetic agent;

or is an anti-obesity agent.

13. The method of claim 12, wherein the second agent is an anti-diabetic agent.

14. The method of claim 12, wherein the second agent is an anti-obesity agent.

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

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

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