title: (+)-4-[2-[4-(8-Chloro-3,10-dibromo-6,11-dihydro-5H-benzo[5, 6]cyclohepta[1,2-b]- pyridin-11(R)-yl)-1-piperidinyl]-2-oxo-ethyl]-1-piperidinecarboxamid e (SCH-66336): a very potent farnesyl protein transferase inhibitor as a novel antitumor agent.
abstract: We have previously shown that appropriate modification of the benzocycloheptapyridine tricyclic ring system can provide potent farnesyl protein transferase (FPT) inhibitors with good cellular activity. Our laboratories have also established that incorporation of either pyridinylacetyl N-oxide or 4-N-carboxamidopiperidinylacetyl moieties results in pharmacokinetically stable inhibitors that are orally efficacious in nude mice. We now demonstrate that further elaboration of the tricyclic ring system by introducing a bromine atom at the 7- or the 10-position of the 3-bromo-8-chlorotricyclic ring system provides compounds that have superior potency and selectivity in FPT inhibition. These compounds have good serum levels and half-lives when given orally to rodents and primates. In vitro and in vivo evaluation of a panel of these inhibitors has led to identification of 15 (SCH 66336) as a highly potent (IC50 = 1.9 nM) antitumor agent that is currently undergoing human clinical trials.
authors.affiliation: Departments of Chemistry and Tumor Biology, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, USA.
authors.forename: F G
authors.initials: FG
authors.lastname: Njoroge
authors.forename: A G
authors.initials: AG
authors.lastname: Taveras
authors.forename: J
authors.initials: J
authors.lastname: Kelly
authors.forename: S
authors.initials: S
authors.lastname: Remiszewski
authors.forename: A K
authors.initials: AK
authors.lastname: Mallams
authors.forename: R
authors.initials: R
authors.lastname: Wolin
authors.forename: A
authors.initials: A
authors.lastname: Afonso
authors.forename: A B
authors.initials: AB
authors.lastname: Cooper
authors.forename: D F
authors.initials: DF
authors.lastname: Rane
authors.forename: Y T
authors.initials: YT
authors.lastname: Liu
authors.forename: J
authors.initials: J
authors.lastname: Wong
authors.forename: B
authors.initials: B
authors.lastname: Vibulbhan
authors.forename: P
authors.initials: P
authors.lastname: Pinto
authors.forename: J
authors.initials: J
authors.lastname: Deskus
authors.forename: C S
authors.initials: CS
authors.lastname: Alvarez
authors.forename: J
authors.initials: J
authors.lastname: del Rosario
authors.forename: M
authors.initials: M
authors.lastname: Connolly
authors.forename: J
authors.initials: J
authors.lastname: Wang
authors.forename: J
authors.initials: J
authors.lastname: Desai
authors.forename: R R
authors.initials: RR
authors.lastname: Rossman
authors.forename: W R
authors.initials: WR
authors.lastname: Bishop
authors.forename: R
authors.initials: R
authors.lastname: Patton
authors.forename: L
authors.initials: L
authors.lastname: Wang
authors.forename: P
authors.initials: P
authors.lastname: Kirschmeier
authors.forename: A K
authors.initials: AK
authors.lastname: Ganguly
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D019556:COS Cells; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D008252:Macaca fascicularis; D051379:Mice; D008819:Mice, Nude; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D017368:Protein Prenylation / Q000187:drug effects*; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D003986:Dibenzocycloheptenes
chemical_list: D019883:Alkyl and Aryl Transferases; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D010880:Piperidines; D011725:Pyridines; C083291:geranylgeranyltransferase type-I; C064911:p21(ras) farnesyl-protein transferase; C115354:lonafarnib; D003986:Dibenzocycloheptenes