title: The discovery of 6-amino nicotinamides as potent and selective histone deacetylase inhibitors.
abstract: This communication highlights the development of a nicotinamide series of histone deacetylase inhibitors within the benzamide structural class. Extensive exploration around the nicotinamide core led to the discovery of a class I selective HDAC inhibitor that possesses excellent intrinsic and cell-based potency, acceptable ancillary pharmacology, favorable pharmacokinetics, sustained pharmacodynamics in vitro, and achieves in vivo efficacy in an HCT116 xenograft model.
authors.affiliation: Department of Drug Design and Optimization-Medicinal Chemistry, Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA. christopher-hamblett@merck.com
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Hamblett
authors.forename: Joey L
authors.initials: JL
authors.lastname: Methot
authors.forename: Dawn M
authors.initials: DM
authors.lastname: Mampreian
authors.forename: David L
authors.initials: DL
authors.lastname: Sloman
authors.forename: Matthew G
authors.initials: MG
authors.lastname: Stanton
authors.forename: Astrid M
authors.initials: AM
authors.lastname: Kral
authors.forename: Judith C
authors.initials: JC
authors.lastname: Fleming
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Cruz
authors.forename: Melissa
authors.initials: M
authors.lastname: Chenard
authors.forename: Nicole
authors.initials: N
authors.lastname: Ozerova
authors.forename: Anna M
authors.initials: AM
authors.lastname: Hitz
authors.forename: Hongmei
authors.initials: H
authors.lastname: Wang
authors.forename: Sujal V
authors.initials: SV
authors.lastname: Deshmukh
authors.forename: Naim
authors.initials: N
authors.lastname: Nazef
authors.forename: Andreas
authors.initials: A
authors.lastname: Harsch
authors.forename: Bethany
authors.initials: B
authors.lastname: Hughes
authors.forename: William K
authors.initials: WK
authors.lastname: Dahlberg
authors.forename: Alex A
authors.initials: AA
authors.lastname: Szewczak
authors.forename: Richard E
authors.initials: RE
authors.lastname: Middleton
authors.forename: Ralph T
authors.initials: RT
authors.lastname: Mosley
authors.forename: J Paul
authors.initials: JP
authors.lastname: Secrist
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Miller
mesh_terms: D015120:6-Aminonicotinamide / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*; D000818:Animals; D019540:Area Under Curve; D001549:Benzamides / Q000737:chemistry; D001682:Biological Availability; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability / Q000187:drug effects; D004285:Dogs; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D006207:Half-Life; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D008958:Models, Molecular; D009368:Neoplasm Transplantation; D011485:Protein Binding; D051381:Rats; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D001549:Benzamides; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D007527:Isoenzymes; D015120:6-Aminonicotinamide