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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
25
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pubmed:dateCreated |
2005-12-12
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pubmed:abstractText |
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.
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pubmed:commentsCorrections |
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Carbazoles,
http://linkedlifedata.com/resource/pubmed/chemical/Histone Deacetylase Inhibitors,
http://linkedlifedata.com/resource/pubmed/chemical/Histone Deacetylases,
http://linkedlifedata.com/resource/pubmed/chemical/Indoles,
http://linkedlifedata.com/resource/pubmed/chemical/NAD,
http://linkedlifedata.com/resource/pubmed/chemical/NAD Nucleosidase,
http://linkedlifedata.com/resource/pubmed/chemical/Niacinamide,
http://linkedlifedata.com/resource/pubmed/chemical/Recombinant Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/SIRT1 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Sirtuin 1,
http://linkedlifedata.com/resource/pubmed/chemical/Sirtuins
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pubmed:status |
MEDLINE
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pubmed:month |
Dec
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pubmed:issn |
0022-2623
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pubmed:author |
pubmed-author:AmouzeghPatriciaP,
pubmed-author:BarkerJonathanJ,
pubmed-author:CurtisRoryR,
pubmed-author:DiStefanoPeter SPS,
pubmed-author:FleggAdamA,
pubmed-author:HamelinEstelleE,
pubmed-author:HixonJeffreyJ,
pubmed-author:JonesStephenS,
pubmed-author:KatesMichaelM,
pubmed-author:KeaveyKennethK,
pubmed-author:McDonaghThomasT,
pubmed-author:NapperAndrew DAD,
pubmed-author:NaviaManuel AMA,
pubmed-author:PonsJean-FrancoisJF,
pubmed-author:SaundersJeffrey OJO,
pubmed-author:ThomasRussell JRJ,
pubmed-author:YauWei TsungWT
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pubmed:issnType |
Print
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pubmed:day |
15
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pubmed:volume |
48
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
8045-54
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pubmed:dateRevised |
2010-7-9
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pubmed:meshHeading |
pubmed-meshheading:16335928-Animals,
pubmed-meshheading:16335928-Biological Availability,
pubmed-meshheading:16335928-CHO Cells,
pubmed-meshheading:16335928-Carbazoles,
pubmed-meshheading:16335928-Cell Membrane Permeability,
pubmed-meshheading:16335928-Cricetinae,
pubmed-meshheading:16335928-Cricetulus,
pubmed-meshheading:16335928-Drug Stability,
pubmed-meshheading:16335928-Fluorometry,
pubmed-meshheading:16335928-Histone Deacetylase Inhibitors,
pubmed-meshheading:16335928-Histone Deacetylases,
pubmed-meshheading:16335928-Humans,
pubmed-meshheading:16335928-Indoles,
pubmed-meshheading:16335928-Kinetics,
pubmed-meshheading:16335928-Mice,
pubmed-meshheading:16335928-Mice, Inbred C57BL,
pubmed-meshheading:16335928-Microsomes, Liver,
pubmed-meshheading:16335928-NAD,
pubmed-meshheading:16335928-NAD+ Nucleosidase,
pubmed-meshheading:16335928-Niacinamide,
pubmed-meshheading:16335928-Rats,
pubmed-meshheading:16335928-Recombinant Proteins,
pubmed-meshheading:16335928-Sirtuin 1,
pubmed-meshheading:16335928-Sirtuins,
pubmed-meshheading:16335928-Stereoisomerism,
pubmed-meshheading:16335928-Structure-Activity Relationship
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pubmed:year |
2005
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pubmed:articleTitle |
Discovery of indoles as potent and selective inhibitors of the deacetylase SIRT1.
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pubmed:affiliation |
Elixir Pharmaceuticals, One Kendall Square, Cambridge, Massachusetts 02139, USA. anapper@elixirpharm.com
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pubmed:publicationType |
Journal Article,
In Vitro
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