title: Design, synthesis, and biological activity of 4-[(4-cyano-2-arylbenzyloxy)-(3-methyl-3H-imidazol-4-yl)methyl]benzonitriles as potent and selective farnesyltransferase inhibitors.
abstract: A novel series of 4-[(4-cyano-2-arylbenzyloxy)-(3-methyl-3H-imidazol-4-yl)methyl]benzonitriles have been synthesized as selective farnesyltransferase inhibitors using structure-based design. X-ray cocrystal structures of compound 20-FTase-HFP and A313326-FTase-HFP confirmed our initial design. The decreased interaction between the aryl groups and Ser 48 in GGTase-I binding site could be one possible reason to explain the improved selectivity for this new series of FTase inhibitors. Medicinal chemistry efforts led to the discovery of compound 64 with potent cellular activity (EC(50) = 3.5 nM) and outstanding pharmacokinetic profiles in dog (96% bioavailable, 18.4 h oral t(1/2), and 0.19 L/(h x kg) plasma clearance).
authors.affiliation: Globe Pharmaceutical R and Abbott Laboratories, 100 Abbott Park Road, Abbott Park, Illinois 60064-6101, USA. le.wang@abbott.com
authors.forename: Le
authors.initials: L
authors.lastname: Wang
authors.forename: Gary T
authors.initials: GT
authors.lastname: Wang
authors.forename: Xilu
authors.initials: X
authors.lastname: Wang
authors.forename: Yunsong
authors.initials: Y
authors.lastname: Tong
authors.forename: Gerry
authors.initials: G
authors.lastname: Sullivan
authors.forename: David
authors.initials: D
authors.lastname: Park
authors.forename: Nicholas M
authors.initials: NM
authors.lastname: Leonard
authors.forename: Qun
authors.initials: Q
authors.lastname: Li
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: Joy L
authors.initials: JL
authors.lastname: Bauch
authors.forename: Clarissa G
authors.initials: CG
authors.lastname: Jakob
authors.forename: Charles W
authors.initials: CW
authors.lastname: Hutchins
authors.forename: Vincent S
authors.initials: VS
authors.lastname: Stoll
authors.forename: Kennan
authors.initials: K
authors.lastname: Marsh
authors.forename: Saul H
authors.initials: SH
authors.lastname: Rosenberg
authors.forename: Hing L
authors.initials: HL
authors.lastname: Sham
authors.forename: Nan-Horng
authors.initials: NH
authors.lastname: Lin
mesh_terms: D000284:Administration, Oral; D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001682:Biological Availability; D002463:Cell Membrane Permeability; D018360:Crystallography, X-Ray; D004285:Dogs; D015195:Drug Design; D051231:Farnesyltranstransferase; D007093:Imidazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D008958:Models, Molecular; D015394:Molecular Structure; D009570:Nitriles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: C482794:5-cyano-2-((4-cyanophenyl)-(3-methyl-3H-imidazol-4-yl)methoxymethyl)-N-phenylbenzamide; D001549:Benzamides; D007093:Imidazoles; D009570:Nitriles; D019883:Alkyl and Aryl Transferases; C083291:geranylgeranyltransferase type-I; D051231:Farnesyltranstransferase