title: Potent, selective, and orally bioavailable tricyclic pyridyl acetamide N-oxide inhibitors of farnesyl protein transferase with enhanced in vivo antitumor activity.
abstract: We previously reported compound 1 as a potent farnesyl protein transferase (FPT) inhibitor that exhibited reasonable pharmacokinetic stability and showed moderate in vivo activity against a variety of tumor cell lines. The analogous C-11 single compound, pyridylacetamide 2, was found to be more potent than 1 in FPT inhibition. Further studies showed that modification of the ethano bridge of the tricyclic ring system by conversion into a double bond with concomitant introduction of a single bond at C-11 piperidine resulted in compound 3 that had superior FPT activity and pharmacokinetic stability. Compound 4, a 5-bromo-substituted analogue of 3, showed improved FPT activity, had good cellular activity, and demonstrated a remarkably improved pharmacokinetic profile with AUC of 84.9 and t1/2 of 82 min. Compound4 inhibited the growth of solid tumor in DLD-1 model by 70% at 50 mpk and 52% at 10 mpk.
authors.affiliation: Schering-Plough Research Institute, Departments of Chemistry and Tumor Biology, 2015 Galloping Hill Road, 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: P
authors.initials: P
authors.lastname: Pinto
authors.forename: W R
authors.initials: WR
authors.lastname: Bishop
authors.forename: M S
authors.initials: MS
authors.lastname: Bryant
authors.forename: A A
authors.initials: AA
authors.lastname: Nomeir
authors.forename: C
authors.initials: C
authors.lastname: Lin
authors.forename: M
authors.initials: M
authors.lastname: Liu
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: D000284:Administration, Oral; D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D001682:Biological Availability; D003497:Cyclic N-Oxides / Q000008:administration & dosage / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D015689:Oncogene Protein p21(ras) / Q000037:antagonists & inhibitors; D011725:Pyridines / Q000008:administration & dosage / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D014407:Tumor Cells, Cultured
chemical_list: C112095:4-(3-bromo-8-chloro-11H-benzo(5,6)cyclohepta(1,2-b)pyridin-11-yl)-1-((4-pyridinyl)acetyl)piperidine N1-oxide; C112096:4-(8-chloro-3,5-dibromo-11H-benzo(5,6)-cyclohepta(1,2-b)pyridin-11-yl)-1-((4-pyridinyl)acetyl)piperidine N1-oxide; C112094:4-(bromo-8-chloro-6,11-dihydro-5H-benzo(5,6)cyclohepta(1,2-b)pyridin-11-yl)-1-((4-pyridinyl)acetyl)piperidine N1-oxide; D000970:Antineoplastic Agents; D003497:Cyclic N-Oxides; D004791:Enzyme Inhibitors; D011725:Pyridines; D019883:Alkyl and Aryl Transferases; C064911:p21(ras) farnesyl-protein transferase; D015689:Oncogene Protein p21(ras)