title: Analogues of 1-(3,10-dibromo-8-chloro-6,11-dihydro-5H-benzo-[5,6]-cyclohepta [1,2-b]pyridin-11-yl)piperidine as inhibitors of farnesyl protein transferase.
abstract: The synthesis of several 4-pyridylacetyl N-oxide derivatives of 4-(3-bromo-6,11-dihydro-5H-benzo[5,6]-cyclohepta[1,2-b]-pyridin-11-yl)pi perazine/piperidine 3 is described. This study was aimed at identifying fomesyl protein transferase (FPT) inhibitors in these two series of tricycles containing different phenyl ring substituents. The in vitro activity profile of the initial group of compounds 7a-7g led to the synthesis of the 8-methyl-10-methoxy and 8-methyl-10-bromo analogues 7i, 13i, and 13j. The 11R(-) enantiomers of these compounds were found to exhibit potent in vitro FPT inhibition activity.
authors.affiliation: Schering-Plough Research Institute, Kenilworth, NJ 07033, USA. adriano.afonso@spcorp.com
authors.forename: A
authors.initials: A
authors.lastname: Afonso
authors.forename: J
authors.initials: J
authors.lastname: Weinstein
authors.forename: J
authors.initials: J
authors.lastname: Kelly
authors.forename: R
authors.initials: R
authors.lastname: Wolin
authors.forename: S B
authors.initials: SB
authors.lastname: Rosenblum
authors.forename: M
authors.initials: M
authors.lastname: Connolly
authors.forename: T
authors.initials: T
authors.lastname: Guzi
authors.forename: L
authors.initials: L
authors.lastname: James
authors.forename: D
authors.initials: D
authors.lastname: Carr
authors.forename: R
authors.initials: R
authors.lastname: Patton
authors.forename: W R
authors.initials: WR
authors.lastname: Bishop
authors.forename: P
authors.initials: P
authors.lastname: Kirshmeier
authors.forename: M
authors.initials: M
authors.lastname: Liu
authors.forename: L
authors.initials: L
authors.lastname: Heimark
authors.forename: K J
authors.initials: KJ
authors.lastname: Chen
authors.forename: A A
authors.initials: AA
authors.lastname: Nomeir
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D010880:Piperidines / Q000737:chemistry* / Q000494:pharmacology; D011725:Pyridines / Q000737:chemistry* / Q000494:pharmacology; D013057:Spectrum Analysis; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D010880:Piperidines; D011725:Pyridines; D019883:Alkyl and Aryl Transferases; C064911:p21(ras) farnesyl-protein transferase