title: Discovery of indoles as potent and selective inhibitors of the deacetylase SIRT1.
abstract: 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.
authors.affiliation: Elixir Pharmaceuticals, One Kendall Square, Cambridge, Massachusetts 02139, USA. anapper@elixirpharm.com
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Napper
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Hixon
authors.forename: Thomas
authors.initials: T
authors.lastname: McDonagh
authors.forename: Kenneth
authors.initials: K
authors.lastname: Keavey
authors.forename: Jean-Francois
authors.initials: JF
authors.lastname: Pons
authors.forename: Jonathan
authors.initials: J
authors.lastname: Barker
authors.forename: Wei Tsung
authors.initials: WT
authors.lastname: Yau
authors.forename: Patricia
authors.initials: P
authors.lastname: Amouzegh
authors.forename: Adam
authors.initials: A
authors.lastname: Flegg
authors.forename: Estelle
authors.initials: E
authors.lastname: Hamelin
authors.forename: Russell J
authors.initials: RJ
authors.lastname: Thomas
authors.forename: Michael
authors.initials: M
authors.lastname: Kates
authors.forename: Stephen
authors.initials: S
authors.lastname: Jones
authors.forename: Manuel A
authors.initials: MA
authors.lastname: Navia
authors.forename: Jeffrey O
authors.initials: JO
authors.lastname: Saunders
authors.forename: Peter S
authors.initials: PS
authors.lastname: DiStefano
authors.forename: Rory
authors.initials: R
authors.lastname: Curtis
mesh_terms: D000818:Animals; D001682:Biological Availability; D016466:CHO Cells; D002227:Carbazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002463:Cell Membrane Permeability; D006224:Cricetinae; D003412:Cricetulus; D004355:Drug Stability; D005470:Fluorometry; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000737:chemistry; D006801:Humans; D066298:In Vitro Techniques; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007700:Kinetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008862:Microsomes, Liver / Q000378:metabolism; D009243:NAD / Q000737:chemistry; D009244:NAD+ Nucleosidase / Q000737:chemistry; D009536:Niacinamide / Q000737:chemistry; D051381:Rats; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry; D056564:Sirtuin 1; D037761:Sirtuins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: C550547:6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide; D002227:Carbazoles; D056572:Histone Deacetylase Inhibitors; D007211:Indoles; D011994:Recombinant Proteins; D009243:NAD; D009536:Niacinamide; D009244:NAD+ Nucleosidase; C447939:SIRT1 protein, human; D056564:Sirtuin 1; D037761:Sirtuins; D006655:Histone Deacetylases