title: Design and synthesis of o-trifluoromethylbiphenyl substituted 2-amino-nicotinonitriles as inhibitors of farnesyltransferase.
abstract: A non-methionine FT inhibitor lead structure (1) was designed through computer modeling of the peptidomimetic FT inhibitor ABT839. Optimization of this lead resulted in compounds 2e and 2g, with FT IC(50) values of 1.3 and 1.8 nM, GGT IC(50) of 1400 nM, and EC(50) (Ras processing) values of 13 and 11 nM, respectively.
authors.affiliation: Global Pharmaceutical Research & Development, Abbott Laboratories, Abbott Park, IL 60064, USA. gary.t.wang@abbott.com
authors.forename: Gary T
authors.initials: GT
authors.lastname: Wang
authors.forename: Xilu
authors.initials: X
authors.lastname: Wang
authors.forename: Weibo
authors.initials: W
authors.lastname: Wang
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Hasvold
authors.forename: Gerry
authors.initials: G
authors.lastname: Sullivan
authors.forename: Charles W
authors.initials: CW
authors.lastname: Hutchins
authors.forename: Steve
authors.initials: S
authors.lastname: O'Conner
authors.forename: Robert
authors.initials: R
authors.lastname: Gentiles
authors.forename: Thomas
authors.initials: T
authors.lastname: Sowin
authors.forename: Jerry
authors.initials: J
authors.lastname: Cohen
authors.forename: Wen-Zhen
authors.initials: WZ
authors.lastname: Gu
authors.forename: Haiying
authors.initials: H
authors.lastname: Zhang
authors.forename: Saul H
authors.initials: SH
authors.lastname: Rosenberg
authors.forename: Hing L
authors.initials: HL
authors.lastname: Sham
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D001713:Biphenyl Compounds / Q000138:chemical synthesis* / Q000494:pharmacology*; D003198:Computer Simulation; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D051231:Farnesyltranstransferase; D007093:Imidazoles; D008958:Models, Molecular; D018716:Molecular Mimicry; D009539:Nicotinic Acids / Q000138:chemical synthesis* / Q000494:pharmacology*; D009570:Nitriles
chemical_list: C478322:4-(3-biphenyl-2-yl-1-hydroxy-1-(3-methyl-3H-imidazol-4-yl)-prop-2-ynyl)-1-yl-benzonitrile; D001713:Biphenyl Compounds; D004791:Enzyme Inhibitors; D007093:Imidazoles; D009539:Nicotinic Acids; D009570:Nitriles; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase