Sirtuin modulating compounds

• US 7,829,556 B2
• Filed: 06/20/2008
• Issued: 11/09/2010
• Est. Priority Date: 06/20/2007
• Status: Expired due to Fees

• Current Assignee: GlaxoSmithKline LLC (GlaxoSmithKline PLC)
• Original Assignee: Sirtris Pharmaceuticals, Inc. (GlaxoSmithKline PLC)
• Inventors: Lunsmann, Walter Joseph, Disch, Jeremy S., Ng, Pui Yee, Vu, Chi B., Jirousek, Michael, Bemis, Jean
• Primary Examiner(s): Andres; Janet L
• Assistant Examiner(s): Robinson; Binta M
• Application Number:
  US12/214,804
• Publication Number:
  US 20090012080A1
• Time in Patent Office: 872 Days
• Field of Search: 544/124, 514/338, 514/233.2
• US Class Current: 514/233.2
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/06 Antigout agents, e.g. antihyperuricemic or uricosuric agents
• CPC Class Codes: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• 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 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/12 Antihypertensives
• CPC Class Codes: C07D 513/04 Ortho-condensed systems

Abstract

Provided herein are novel sirtuin-modulating compounds and methods of use thereof. The sirtuin-modulating compounds may be used for increasing the lifespan of a cell, and treating and/or preventing a wide variety of diseases and disorders including, for example, diseases or disorders related to aging or stress, diabetes, obesity, neurodegenerative diseases, cardiovascular disease, blood clotting disorders, inflammation, cancer, and/or flushing as well as diseases or disorders that would benefit from increased mitochondrial activity. Also provided are compositions comprising a sirtuin-modulating compound in combination with another therapeutic agent.

Claims

1. A compound represented by Structural Formula (V):

2. The compound of claim 1, wherein the compound is a free base.

3. The compound of claim 1, wherein the compound is a salt.

4. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt of claim 1 and a pharmaceutically acceptable carrier.

5. The composition of claim 4, wherein the pharmaceutical composition is pyrogen-free.

6. The composition of claim 4, further comprising an additional active agent.

7. A method for treating insulin resistance, a metabolic syndrome, diabetes, or complications thereof, or for increasing insulin sensitivity in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of at least one pharmaceutical composition of claim 4.

8. The method of claim 7, wherein said compound increases at least one of the level or activity of a sirtuin protein.

9. The method of claim 8, wherein the compound increases deacetylase activity of the sirtuin protein.

10. The method of claim 8, wherein the sirtuin protein is a mammalian protein.

11. The method of claim 8, wherein the sirtuin protein is human SIRT1.

12. The method of claim 8, wherein the compound does not substantially have one or more of the following activities:

inhibition of PI3-kinase, inhibition of aldoreductase, inhibition of tyrosine kinase, transactivation of EGFR tyrosine kinase, coronary dilation, or spasmolytic activity, at concentrations of the compound that are effective for increasing the deacetylation activity of a SIRT1 and/or SIRT3 protein.