Discovery of oxazolo[4,5-b]pyridines and related heterocyclic analogs as novel SIRT1 activators.
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.
Bemis
Jean E
JE
Sirtris, A GSK Company, Cambridge, MA 01239, USA. jean_bemis@comcast.net
Vu
Chi B
CB
Xie
Roger
R
Nunes
Joseph J
JJ
Ng
Pui Yee
PY
Disch
Jeremy S
JS
Milne
Jill C
JC
Carney
David P
DP
Lynch
Amy V
AV
Jin
Lei
L
Smith
Jesse J
JJ
Lavu
Siva
S
Iffland
Andre
A
Jirousek
Michael R
MR
Perni
Robert B
RB
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
D019086:Bridged Bicyclo Compounds, Heterocyclic; D010080:Oxazoles; D011725:Pyridines; C447939:SIRT1 protein, human; D056564:Sirtuin 1; D037761:Sirtuins