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

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J Med Chem. 2005 Dec 15;48(25):8045-54.

Discovery of Indoles as Potent and Selective

Inhibitors of the Deacetylase SIRT1.

Napper AD, Hixon J, McDonagh T, Keavey K, Pons JF,

Barker J, Yau WT, Amouzegh P, Flegg A, Hamelin E,

RJ, Kates M, S, Navia MA, Saunders JO,

Distefano PS, Curtis R.

Elixir Pharmaceuticals, One Kendall Square, Cambridge,

Massachusetts 02139, EvotecOAI, 151 Milton Park,

Abingdon OX14 4SD, U.K., and Advanced Synthesis Group,

Newark, Delaware 19711.

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 IC(50) 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.

PMID: 16335928 [PubMed - in process]

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