title: Structure-activity relationship of 3-substituted N-(pyridinylacetyl)-4- (8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene )- piperidine inhibitors of farnesyl-protein transferase: design and synthesis of in vivo active antitumor compounds.
abstract: Novel tricyclic Ras farnesyl-protein transferase (FPT) inhibitors are described. A comprehensive structure-activity relationship (SAR) study of compounds arising from substitution at the 3-position of the tricyclic pyridine ring system has been explored. In the case of halogens, the chloro, bromo, and iodo analogues 19, 22, and 28 were found to be equipotent. However, the fluoro analogue 17 was an order of magnitude less active. Whereas a small alkyl substituent such as a methyl group resulted in a very potent FPT inhibitor (SCH 56580), introduction of bulky substituents such as tert-butyl, compound 33, or a phenyl group, compound 29, resulted in inactive FPT inhibitors. Polar groups at the 3-position such as amino 5, alkylamino 6, and hydroxyl 12 were less active. Whereas compound SCH 44342 did not show appreciable in vivo antitumor activity, the 3-bromo-substituted pyridyl N-oxide amide analogue 38 was a potent FPT inhibitor that reduced tumor growth by 81% when administered q.i.d. at 50 mpk and 52% at 10 mpk. These compounds are nonpeptidic and do not contain sulfhydryl groups. They selectively inhibit FPT and not geranylgeranyl-protein transferase-1 (GGPT-1). They also inhibit H-Ras processing in COS monkey kidney cells and soft agar growth of Ras-transformed cells.
authors.affiliation: Department of Chemistry, Schering-Plough Research Institute, Kenilworth, New Jersey 07033, USA.
authors.forename: F G
authors.initials: FG
authors.lastname: Njoroge
authors.forename: B
authors.initials: B
authors.lastname: Vibulbhan
authors.forename: D F
authors.initials: DF
authors.lastname: Rane
authors.forename: W R
authors.initials: WR
authors.lastname: Bishop
authors.forename: J
authors.initials: J
authors.lastname: Petrin
authors.forename: R
authors.initials: R
authors.lastname: Patton
authors.forename: M S
authors.initials: MS
authors.lastname: Bryant
authors.forename: K J
authors.initials: KJ
authors.lastname: Chen
authors.forename: A A
authors.initials: AA
authors.lastname: Nomeir
authors.forename: C C
authors.initials: CC
authors.lastname: Lin
authors.forename: M
authors.initials: M
authors.lastname: Liu
authors.forename: I
authors.initials: I
authors.lastname: King
authors.forename: J
authors.initials: J
authors.lastname: Chen
authors.forename: S
authors.initials: S
authors.lastname: Lee
authors.forename: B
authors.initials: B
authors.lastname: Yaremko
authors.forename: J
authors.initials: J
authors.lastname: Dell
authors.forename: P
authors.initials: P
authors.lastname: Lipari
authors.forename: M
authors.initials: M
authors.lastname: Malkowski
authors.forename: Z
authors.initials: Z
authors.lastname: Li
authors.forename: J
authors.initials: J
authors.lastname: Catino
authors.forename: R J
authors.initials: RJ
authors.lastname: Doll
authors.forename: V
authors.initials: V
authors.lastname: Girijavallabhan
authors.forename: A K
authors.initials: AK
authors.lastname: Ganguly
mesh_terms: D016475:3T3 Cells; D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D019556:COS Cells; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008819:Mice, Nude; D015394:Molecular Structure; D009374:Neoplasms, Experimental / Q000188:drug therapy; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017368:Protein Prenylation; D011725:Pyridines / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014162:Transfection / Q000235:genetics; D018631:ras Proteins / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D010880:Piperidines; D011725:Pyridines; D019883:Alkyl and Aryl Transferases; C083291:geranylgeranyltransferase type-I; C064911:p21(ras) farnesyl-protein transferase; D018631:ras Proteins