Discovery of Indoles as Potent and Selective Inhibitors of the Deacetylase SIRT1

• Published in: Journal of medicinal chemistry 2005-12, Vol.48 (25), p.8045-8054
• Main 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
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Biological Availability; Carbazoles - chemical synthesis; Carbazoles - chemistry; Carbazoles - pharmacology; Cell Membrane Permeability; CHO Cells; Cricetinae; Cricetulus; Drug Stability; Fluorometry; Histone Deacetylase Inhibitors; Histone Deacetylases - chemistry; Humans; In Vitro Techniques; Indoles - chemical synthesis; Indoles - chemistry; Indoles - pharmacology; Kinetics; Medical sciences; Mice; Mice, Inbred C57BL; Microsomes, Liver - metabolism; Miscellaneous; NAD - chemistry; NAD+ Nucleosidase - chemistry; Niacinamide - chemistry; Pharmacology. Drug treatments; Rats; Recombinant Proteins - antagonists & inhibitors; Recombinant Proteins - chemistry; Sirtuin 1; Sirtuins - antagonists & inhibitors; Sirtuins - chemistry; Stereoisomerism; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm050522v

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.