title: Second-generation peptidomimetic inhibitors of protein farnesyltransferase demonstrating improved cellular potency and significant in vivo efficacy.
abstract: The synthesis and evaluation of analogues of previously reported farnesyltransferase inhibitors, pyridyl benzyl ether 3 and pyridylbenzylamine 4, are described. Substitution of 3 at the 5-position of the core aryl ring resulted in inhibitors of equal or less potency against the enzyme and decreased efficacy in a cellular assay against Ras processing by the enzyme. Substitution of 4 at the benzyl nitrogen yielded 26, which showed improved efficacy and potency and yet presented a poor pharmacokinetic profile. Further modification afforded 30, which demonstrated a dramatically improved pharmacokinetic profile. Compounds 26 and 29 demonstrated significant in vivo efficacy in nude mice inoculated with MiaPaCa-2, a human pancreatic tumor-derived cell line.
authors.affiliation: Department of Cancer Research D-47B, Abbott Laboratories, Abbott Park, Illinois 60064-3500, USA.
authors.forename: S J
authors.initials: SJ
authors.lastname: O'Connor
authors.forename: K J
authors.initials: KJ
authors.lastname: Barr
authors.forename: L
authors.initials: L
authors.lastname: Wang
authors.forename: B K
authors.initials: BK
authors.lastname: Sorensen
authors.forename: A S
authors.initials: AS
authors.lastname: Tasker
authors.forename: H
authors.initials: H
authors.lastname: Sham
authors.forename: S C
authors.initials: SC
authors.lastname: Ng
authors.forename: J
authors.initials: J
authors.lastname: Cohen
authors.forename: E
authors.initials: E
authors.lastname: Devine
authors.forename: S
authors.initials: S
authors.lastname: Cherian
authors.forename: B
authors.initials: B
authors.lastname: Saeed
authors.forename: H
authors.initials: H
authors.lastname: Zhang
authors.forename: J Y
authors.initials: JY
authors.lastname: Lee
authors.forename: R
authors.initials: R
authors.lastname: Warner
authors.forename: S
authors.initials: S
authors.lastname: Tahir
authors.forename: P
authors.initials: P
authors.lastname: Kovar
authors.forename: P
authors.initials: P
authors.lastname: Ewing
authors.forename: J
authors.initials: J
authors.lastname: Alder
authors.forename: M
authors.initials: M
authors.lastname: Mitten
authors.forename: J
authors.initials: J
authors.lastname: Leal
authors.forename: K
authors.initials: K
authors.lastname: Marsh
authors.forename: J
authors.initials: J
authors.lastname: Bauch
authors.forename: D J
authors.initials: DJ
authors.lastname: Hoffman
authors.forename: S M
authors.initials: SM
authors.lastname: Sebti
authors.forename: S H
authors.initials: SH
authors.lastname: Rosenberg
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology; D001596:Benzylamines / Q000138:chemical synthesis / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D004987:Ethers / Q000138:chemical synthesis / Q000494:pharmacology; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured; D019014:fas Receptor
chemical_list: D000970:Antineoplastic Agents; D001596:Benzylamines; D004791:Enzyme Inhibitors; D004987:Ethers; C491901:FAS protein, human; C491899:Fas protein, mouse; D009479:Neuropeptides; D018124:Receptors, Tumor Necrosis Factor; D019014:fas Receptor; D019883:Alkyl and Aryl Transferases; C064911:p21(ras) farnesyl-protein transferase