Discovery of imidazo[1,2-b]thiazole derivatives as novel SIRT1 activators.
A series of imidazo[1,2-b]thiazole derivatives is shown to activate the NAD(+)-dependent deacetylase SIRT1, a potential new therapeutic target to treat various metabolic disorders. This series of compounds was derived from a high throughput screening hit bearing an oxazolopyridine core. Water-solubilizing groups could be installed conveniently at either the C-2 or C-3 position of the imidazo[1,2-b]thiazole ring. The SIRT1 enzyme activity could be adjusted by modifying the amide portion of these imidazo[1,2-b]thiazole derivatives. The most potent analogue within this series, namely, compound 29, has demonstrated oral antidiabetic activity in the ob/ob mouse model, the diet-induced obesity (DIO) mouse model, and the Zucker fa/fa rat model.
Vu
Chi B
CB
Sirtris Pharmaceuticals, Cambridge, Massachusetts 02139, USA. cvu@sirtrispharma.com
Bemis
Jean E
JE
Disch
Jeremy S
JS
Ng
Pui Yee
PY
Nunes
Joseph J
JJ
Milne
Jill C
JC
Carney
David P
DP
Lynch
Amy V
AV
Smith
Jesse J
JJ
Lavu
Siva
S
Lambert
Philip D
PD
Gagne
David J
DJ
Jirousek
Michael R
MR
Schenk
Simon
S
Olefsky
Jerrold M
JM
Perni
Robert B
RB
D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D020536:Enzyme Activators / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D011810:Quinoxalines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D011924:Rats, Zucker; D056564:Sirtuin 1 / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D020536:Enzyme Activators; D007004:Hypoglycemic Agents; D007093:Imidazoles; C550359:N-(2-(3-(piperazin-1-ylmethyl)imidazo(2,1-b)thiazol-6-yl)phenyl)quinoxaline-2-carboxamide; D011810:Quinoxalines; D013844:Thiazoles; C470545:Sirt1 protein, mouse; C488368:Sirt1 protein, rat; D056564:Sirtuin 1