2. Academic Validation
  3. Discovery of indoles as potent and selective inhibitors of the deacetylase SIRT1

Discovery of indoles as potent and selective inhibitors of the deacetylase SIRT1

  • J Med Chem. 2005 Dec 15;48(25):8045-54. doi: 10.1021/jm050522v.
Andrew D Napper 1,  Jeffrey Hixon,  Thomas McDonagh,  Kenneth Keavey,  Jean-Francois Pons,  Jonathan Barker,  Wei Tsung Yau,  Patricia Amouzegh,  Adam Flegg,  Estelle Hamelin,  Russell J Thomas,  Michael Kates,  Stephen Jones,  Manuel A Navia,  Jeffrey O Saunders,  Peter S DiStefano,  Rory Curtis
Affiliations

Affiliation

  • 1 Elixir Pharmaceuticals, One Kendall Square, Cambridge, Massachusetts 02139, USA. anapper@elixirpharm.com
PMID: 16335928 DOI: 10.1021/jm050522v
Abstract

High-throughput screening against the human Sirtuin SIRT1 led to the discovery of a series of indoles as potent inhibitors that are selective for SIRT1 over other deacetylases and NAD-processing Enzymes. The most potent compounds described herein inhibit SIRT1 with IC50 values of 60-100 nM, representing a 500-fold improvement over previously reported SIRT inhibitors. Preparation of enantiomerically pure indole derivatives allowed for their characterization in vitro and in vivo. Kinetic analyses suggest that these inhibitors bind after the release of nicotinamide from the Enzyme and prevent the release of deacetylated peptide and O-acetyl-ADP-ribose, the products of enzyme-catalyzed deacetylation. These SIRT1 inhibitors are low molecular weight, cell-permeable, orally bioavailable, and metabolically stable. These compounds provide chemical tools to study the biology of SIRT1 and to explore therapeutic uses for SIRT1 inhibitors.

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