title: Discovery of imidazo[1,2-b]thiazole derivatives as novel SIRT1 activators.
abstract: 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.
authors.affiliation: Sirtris Pharmaceuticals, Cambridge, Massachusetts 02139, USA. cvu@sirtrispharma.com
authors.forename: Chi B
authors.initials: CB
authors.lastname: Vu
authors.forename: Jean E
authors.initials: JE
authors.lastname: Bemis
authors.forename: Jeremy S
authors.initials: JS
authors.lastname: Disch
authors.forename: Pui Yee
authors.initials: PY
authors.lastname: Ng
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Nunes
authors.forename: Jill C
authors.initials: JC
authors.lastname: Milne
authors.forename: David P
authors.initials: DP
authors.lastname: Carney
authors.forename: Amy V
authors.initials: AV
authors.lastname: Lynch
authors.forename: Jesse J
authors.initials: JJ
authors.lastname: Smith
authors.forename: Siva
authors.initials: S
authors.lastname: Lavu
authors.forename: Philip D
authors.initials: PD
authors.lastname: Lambert
authors.forename: David J
authors.initials: DJ
authors.lastname: Gagne
authors.forename: Michael R
authors.initials: MR
authors.lastname: Jirousek
authors.forename: Simon
authors.initials: S
authors.lastname: Schenk
authors.forename: Jerrold M
authors.initials: JM
authors.lastname: Olefsky
authors.forename: Robert B
authors.initials: RB
authors.lastname: Perni
mesh_terms: 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
chemical_list: 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