The sirtuins are an ubiquitous, highly conserved family of seven NAD+-dependent deacylases (SIRT1-7) that may have evolved as cellular energy sensors.  Mammalian SIRT1 regulates key metabolic and inflammatory pathways by deacetylating several endogenous substrates including PGC-1a, NF-kB and FOXO transcription factors.  Increasing SIRT1 activity by overexpression or chemical activation has shown protection against various disease states including diet-induced insulin resistance, suppression of tumors, and improvement in cardiac and vascular function.  Sirtris has developed small-molecule SIRT1-activating compounds (STACs) that modulate metabolic and inflammatory disease markers in rodent models.  Evolution of the chemical scaffolds initially identified through high-throughput screening has led to compounds in structurally distinct series that increase SIRT1 deacetylase activity.  The quinoline series will be discussed, including SAR and optimization of physicochemical properties.   SIRT1 activation by two distinct quinoline frameworks, differing in connectivity of the substituents to the quinoline core, highlights the importance of side chain proximity for SIRT1 activation.

Activation of SIRT1 by 2,8-disubstituted quinolines: SAR and physicochemical properties

245th National Meeting (2013)

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