title: Bridgehead modification of trihalocycloheptabenzopyridine leads to a potent farnesyl protein transferase inhibitor with improved oral metabolic stability.
abstract: Modification of the ethano bridge of the core structure of the antitumor agent, SARASAR (SCH66336) with concomitant introduction of a sulfonamide moiety off the distal piperidine afforded inhibitor 9-(S-), a compound with greatly improved PK profile. Other compounds with enhanced FPTase inhibitory activity were obtained as exemplified by amide 10-(S-) and urea 11-(S-): these compounds demonstrated activity in picomolar range.
authors.affiliation: Schering-Plough Research Institute, 2015 Galloping Hill Road, K-15-3-3545, Kenilworth, NJ 07033, USA. george.njoroge@spcorp.com
authors.forename: F George
authors.initials: FG
authors.lastname: Njoroge
authors.forename: Bancha
authors.initials: B
authors.lastname: Vibulbhan
authors.forename: Xiongwei
authors.initials: X
authors.lastname: Shi
authors.forename: Corey
authors.initials: C
authors.lastname: Strickland
authors.forename: Paul
authors.initials: P
authors.lastname: Kirschmeier
authors.forename: Robert
authors.initials: R
authors.lastname: Bishop
authors.forename: Amin
authors.initials: A
authors.lastname: Nomeir
authors.forename: Viyyoor
authors.initials: V
authors.lastname: Girijavallabhan
mesh_terms: D000284:Administration, Oral; D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004355:Drug Stability; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000737:chemistry* / Q000378:metabolism; D008968:Molecular Conformation; D011485:Protein Binding / Q000502:physiology; D011725:Pyridines / Q000008:administration & dosage / Q000737:chemistry* / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D011725:Pyridines; D019883:Alkyl and Aryl Transferases; C064911:p21(ras) farnesyl-protein transferase