Sirtuin modulating compounds
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 benfit from increased mitochondrial activity. Also provided are compositions comprising a sirtuin-modulating compound in combination with another therapeutic agent.
1. A compound represented by Structural Formula (III):
or a salt thereof, wherein:
R is —H or CH 3 ;
R 1 is a substituted or unsubstituted nitrogen-containing heterocyclylmethyl group;
R 2 is —H or —CH 3 ; and
R 3 is an unsubstituted pyridyl group.
2. The compound of claim 1 , wherein the heterocyclylmethyl group contains a nitrogen atom and optionally a second heteroatom selected from nitrogen and oxygen.
3. The compound of claim 2 , wherein R 1 is a (substituted or unsubstituted non-aromatic heterocyclyl)methyl group.
4. The compound of claim 3 , wherein R 1 is a morpholinomethyl group.
5. The compound of claim 1 , wherein R 1 is a 1,2,4-triazolylmethyl group.
6. The compound of claim 1 , wherein the compound is represented by Structural Formula (IV):
or a salt thereof.
7. The compound of claim 6 , wherein the heterocyclylmethyl group contains a nitrogen atom and optionally a second heteroatom selected from nitrogen and oxygen.
8. The compound of claim 7 , wherein R 1 is a (substituted or unsubstituted non-aromatic heterocyclyl)methyl group.
9. The compound of claim 6 , wherein the compound is represented by Structural Formula (VI):
or a salt thereof.
10. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt of claim 1 and a pharmaceutically acceptable carrier.
11. The composition of claim 10 , wherein the pharmaceutical composition is pyrogen-free.
12. The composition of claim 10 , further comprising an additional active agent.
13. A method for treating insulin resistance, metabolic syndrome, or diabetes, 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 10 .
14. The method of claim 13 , wherein said compound increases at least one of the level or activity of a sirtuin protein.
15. The method of claim 14 , wherein the compound increases deacetylase activity of the sirtuin protein.
16. The method of claim 14 , wherein the sirtuin protein is a mammalian protein.
17. The method of claim 14 , wherein the sirtuin protein is human SIRT1.