title: Discovery of bicyclic pyrazoles as class III histone deacetylase SIRT1 and SIRT2 inhibitors.
abstract: A series of bicyclic pyrazole carboxamides was synthesized and tested for inhibitory activity against the class III deacetylase sirtuin enzymes. Moderate to low micromolar inhibitory activities were obtained against SIRT1 and SIRT2. These bicyclic pyrazole compounds represent a new class of sirtuin inhibitors with a preference for SIRT1 over SIRT2.
authors.affiliation: Department of Medicinal Chemistry, MethylGene Inc., 7150 rue Frederick-Banting, Montreal, QC H4S 2A1, Canada. Electronic address: eric@molecularforecaster.com.
authors.forename: Eric
authors.initials: E
authors.lastname: Therrien
authors.affiliation: Department of Medicinal Chemistry, MethylGene Inc., 7150 rue Frederick-Banting, Montreal, QC H4S 2A1, Canada.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Larouche
authors.affiliation: Department of Medicinal Chemistry, MethylGene Inc., 7150 rue Frederick-Banting, Montreal, QC H4S 2A1, Canada.
authors.forename: Natalie
authors.initials: N
authors.lastname: Nguyen
authors.affiliation: Department of Lead Discovery, MethylGene Inc., 7150 rue Frederick-Banting, Montreal, QC H4S 2A1, Canada.
authors.forename: Jubrail
authors.initials: J
authors.lastname: Rahil
authors.affiliation: Department of Lead Discovery, MethylGene Inc., 7150 rue Frederick-Banting, Montreal, QC H4S 2A1, Canada.
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Lemieux
authors.affiliation: Department of Molecular Biology, MethylGene Inc., 7150 rue Frederick-Banting, Montreal, QC H4S 2A1, Canada.
authors.forename: Zuomei
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Molecular Biology, MethylGene Inc., 7150 rue Frederick-Banting, Montreal, QC H4S 2A1, Canada.
authors.forename: Marielle
authors.initials: M
authors.lastname: Fournel
authors.affiliation: Department of Molecular Biology, MethylGene Inc., 7150 rue Frederick-Banting, Montreal, QC H4S 2A1, Canada.
authors.forename: Theresa P
authors.initials: TP
authors.lastname: Yan
authors.affiliation: Department of Molecular Biology, MethylGene Inc., 7150 rue Frederick-Banting, Montreal, QC H4S 2A1, Canada.
authors.forename: Anne-Julie
authors.initials: AJ
authors.lastname: Landry
authors.affiliation: Department of Molecular Biology, MethylGene Inc., 7150 rue Frederick-Banting, Montreal, QC H4S 2A1, Canada.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Lefebvre
authors.affiliation: Department of Molecular Biology, MethylGene Inc., 7150 rue Frederick-Banting, Montreal, QC H4S 2A1, Canada.
authors.forename: James J
authors.initials: JJ
authors.lastname: Wang
authors.affiliation: Celgene Inc., 4550 Towne Centre Court, San Diego, CA 92121, United States.
authors.forename: Kyle
authors.initials: K
authors.lastname: MacBeth
authors.affiliation: Celgene Inc., 4550 Towne Centre Court, San Diego, CA 92121, United States.
authors.forename: Carla
authors.initials: C
authors.lastname: Heise
authors.affiliation: Celgene Inc., 4550 Towne Centre Court, San Diego, CA 92121, United States.
authors.forename: Aaron
authors.initials: A
authors.lastname: Nguyen
authors.affiliation: Department of Molecular Biology, MethylGene Inc., 7150 rue Frederick-Banting, Montreal, QC H4S 2A1, Canada.
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Besterman
authors.affiliation: Department of Medicinal Chemistry, MethylGene Inc., 7150 rue Frederick-Banting, Montreal, QC H4S 2A1, Canada.
authors.forename: Robert
authors.initials: R
authors.lastname: Déziel
authors.affiliation: Department of Medicinal Chemistry, MethylGene Inc., 7150 rue Frederick-Banting, Montreal, QC H4S 2A1, Canada.
authors.forename: Amal
authors.initials: A
authors.lastname: Wahhab
mesh_terms: D001665:Binding Sites; D001643:Bridged Bicyclo Compounds / Q000737:chemistry*; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D004353:Drug Evaluation, Preclinical; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D056565:Sirtuin 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D001643:Bridged Bicyclo Compounds; D011720:Pyrazoles; D056564:Sirtuin 1; D056565:Sirtuin 2
keywords: Docking; Inhibitor; Pyrazole; SIRT; Sirtuin