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.