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

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, represen...

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Bibliographic Details
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
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Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm050522v