title: Discovery of oxazolo[4,5-b]pyridines and related heterocyclic analogs as novel SIRT1 activators.
abstract: SIRT1 is an NAD(+)-dependent protein deacetylase that appears to produce beneficial effects on metabolic parameters such as glucose and insulin homeostasis. Activation of SIRT1 by resveratrol (1) has been shown to modulate insulin resistance, increase mitochondrial content and prolong survival in lower organisms and in mice on a high fat diet. Herein, we describe the identification and SAR of a series of oxazolo[4,5-b]pyridines as novel small molecule activators of SIRT1 which are structurally unrelated to and more potent than resveratrol.
authors.affiliation: Sirtris, A GSK Company, Cambridge, MA 01239, USA. jean_bemis@comcast.net
authors.forename: Jean E
authors.initials: JE
authors.lastname: Bemis
authors.forename: Chi B
authors.initials: CB
authors.lastname: Vu
authors.forename: Roger
authors.initials: R
authors.lastname: Xie
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Nunes
authors.forename: Pui Yee
authors.initials: PY
authors.lastname: Ng
authors.forename: Jeremy S
authors.initials: JS
authors.lastname: Disch
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: Lei
authors.initials: L
authors.lastname: Jin
authors.forename: Jesse J
authors.initials: JJ
authors.lastname: Smith
authors.forename: Siva
authors.initials: S
authors.lastname: Lavu
authors.forename: Andre
authors.initials: A
authors.lastname: Iffland
authors.forename: Michael R
authors.initials: MR
authors.lastname: Jirousek
authors.forename: Robert B
authors.initials: RB
authors.lastname: Perni
mesh_terms: D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D010080:Oxazoles / Q000138:chemical synthesis* / Q000378:metabolism* / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis* / Q000378:metabolism* / Q000494:pharmacology; D051381:Rats; D011924:Rats, Zucker; D056564:Sirtuin 1; D037761:Sirtuins / Q000819:agonists / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; D010080:Oxazoles; D011725:Pyridines; C447939:SIRT1 protein, human; D056564:Sirtuin 1; D037761:Sirtuins