50639-66-2Relevant articles and documents
Discovery of indoles as potent and selective inhibitors of the deacetylase SIRT1
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
, p. 8045 - 8054 (2007/10/03)
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.
METHODS OF TREATING DISORDER
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Page/Page column 29, (2008/06/13)
Compound of formula (I) and methods of treating disorders by administering a compound of formula (I) are described herein. Examples of disorders include neoplastic disorders, fat-cell related disorders, neurodegenerative disorders, and metabolic disorders
