Discovery of indoles as potent and selective inhibitors of the deacetylase SIRT1 |
| |
Authors: | Napper Andrew D Hixon Jeffrey McDonagh Thomas Keavey Kenneth Pons Jean-Francois Barker Jonathan Yau Wei Tsung Amouzegh Patricia Flegg Adam Hamelin Estelle Thomas Russell J Kates Michael Jones Stephen Navia Manuel A Saunders Jeffrey O DiStefano Peter S Curtis Rory |
| |
Institution: | Elixir Pharmaceuticals, One Kendall Square, Cambridge, Massachusetts 02139, USA. anapper@elixirpharm.com |
| |
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. |
| |
Keywords: | |
本文献已被 PubMed 等数据库收录! |
|