Thiazolopyridine sirtuin modulating compounds
Provided herein are novel sirtuin-modulating compounds of Structural Formula (Ia) 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.
1. A compound represented by Structural Formula (Ia):
or a pharmaceutically acceptable salt thereof, wherein:
ring A is selected from
wherein “*” represents a portion of ring A bound to phenyl, and “ ” represents a portion of ring A bound to C═O in the compound;
R 1 is selected from hydrogen,
R 3 is selected from hydrogen, methoxypropyl, methoxyprop-1-ynyl,
at least one of R 1 or R 3 comprises a nitrogen-containing saturated heterocyclyl portion.
2. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
3. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
4. The compound of claim 1 , wherein the compound is represented by Structural Formula (III):
or a pharmaceutically acceptable salt thereof.
5. The compound of claim 4 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
6. A compound represented by Structural Formula (VI):
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is selected from hydrogen,
R 3 is selected from hydrogen, —CH 3 , —CF 3 , methoxypropyl, methoxyprop-1-ynyl,
at least one of R 1 or R 3 comprises a nitrogen-containing saturated heterocyclyl portion.
7. The compound of claim 6 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
8. The compound of claim 6 , wherein:
R 1 is selected from
and R 3 is selected from hydrogen, —CF 3 and —CH 3 .
9. The compound of claim 8 , wherein R 3 is hydrogen.
10. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
11. The composition of claim 10 , wherein the pharmaceutical composition is pyrogen-free.
12. The composition of claim 11 , further comprising an additional active agent.
13. A method for treating a subject suffering from or susceptible to insulin resistance, a metabolic syndrome, diabetes, or for increasing insulin sensitivity in a subject, comprising administering to the subject in need thereof a composition of claim 10 .