title: Design and biological activity of (S)-4-(5-([1-(3-chlorobenzyl)-2-oxopyrrolidin-3-ylamino]methyl)imidazol-1-ylmethyl)benzonitrile, a 3-aminopyrrolidinone farnesyltransferase inhibitor with excellent cell potency.
abstract: The synthesis, structure-activity relationships, and biological properties of a novel series of imidazole-containing inhibitors of farnesyltransferase are described. Starting from a 3-aminopyrrolidinone core, a systematic series of modifications provided 5h, a non-thiol, non-peptide farnesyltransferase inhibitor with excellent bioavailability in dogs. Compound 5h was found to have an unusually favorable ratio of cell potency to intrinsic potency, compared with other known FTIs. It exhibited excellent potency against a range of tumor cell lines in vitro and showed full efficacy in the K-rasB transgenic mouse model.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, West Point, Pennsylvania 19486, USA. ian_bell@merck.com
authors.forename: I M
authors.initials: IM
authors.lastname: Bell
authors.forename: S N
authors.initials: SN
authors.lastname: Gallicchio
authors.forename: M
authors.initials: M
authors.lastname: Abrams
authors.forename: D C
authors.initials: DC
authors.lastname: Beshore
authors.forename: C A
authors.initials: CA
authors.lastname: Buser
authors.forename: J C
authors.initials: JC
authors.lastname: Culberson
authors.forename: J
authors.initials: J
authors.lastname: Davide
authors.forename: M
authors.initials: M
authors.lastname: Ellis-Hutchings
authors.forename: C
authors.initials: C
authors.lastname: Fernandes
authors.forename: J B
authors.initials: JB
authors.lastname: Gibbs
authors.forename: S L
authors.initials: SL
authors.lastname: Graham
authors.forename: G D
authors.initials: GD
authors.lastname: Hartman
authors.forename: D C
authors.initials: DC
authors.lastname: Heimbrook
authors.forename: C F
authors.initials: CF
authors.lastname: Homnick
authors.forename: J R
authors.initials: JR
authors.lastname: Huff
authors.forename: K
authors.initials: K
authors.lastname: Kassahun
authors.forename: K S
authors.initials: KS
authors.lastname: Koblan
authors.forename: N E
authors.initials: NE
authors.lastname: Kohl
authors.forename: R B
authors.initials: RB
authors.lastname: Lobell
authors.forename: J J
authors.initials: JJ
authors.lastname: Lynch
authors.forename: P A
authors.initials: PA
authors.lastname: Miller
authors.forename: C A
authors.initials: CA
authors.lastname: Omer
authors.forename: A D
authors.initials: AD
authors.lastname: Rodrigues
authors.forename: E S
authors.initials: ES
authors.lastname: Walsh
authors.forename: T M
authors.initials: TM
authors.lastname: Williams
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D001667:Binding, Competitive; D001682:Biological Availability; D002461:Cell Line, Transformed; D004285:Dogs; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051231:Farnesyltranstransferase; D011905:Genes, ras; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007769:Lactams / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D008958:Models, Molecular; D009374:Neoplasms, Experimental / Q000473:pathology; D009570:Nitriles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011760:Pyrrolidinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: C435192:4-(5-((1-(3-chlorobenzyl)-2-oxopyrrolidin-3-ylamino)methyl)imidazol-1-ylmethyl)benzonitrile; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D007093:Imidazoles; D007769:Lactams; D009570:Nitriles; D011760:Pyrrolidinones; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase