title: Discovery and structure-activity relationships of novel piperidine inhibitors of farnesyltransferase.
abstract: A novel piperidine series of farnesyltransferase (FTase) inhibitors is described. Systematic medicinal chemistry studies starting with the lead compound, discovered from a 5-nitropiperidin-2-one combinatorial library, resulted in a potent series of novel FTase inhibitors. We found that all of four substituents of the piperidine core played an important role for FTase inhibition. A 10-fold increase in potency was observed by changing the piperidine-2-one core to the corresponding piperidine core. This class of compounds was found to inhibit farnesyltransferase in a Ras competitive manner. Optical resolution of several potent inhibitors revealed that the (+)-enantiomers showed potent farnesyltransferase inhibition. (+)-8 inhibited FTase with an IC(50) of 1.9 nM.
authors.affiliation: Pharmaceutical Research Institute, Kyowa Hakko Kogyo Co., Ltd., 1188 Shimotogari, Nagaizumi-cho, Shizuoka 411-8731, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Nara
authors.forename: Rieko
authors.initials: R
authors.lastname: Tanaka
authors.forename: Jun
authors.initials: J
authors.lastname: Eishima
authors.forename: Mitsunobu
authors.initials: M
authors.lastname: Hara
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Takahashi
authors.forename: Shizuo
authors.initials: S
authors.lastname: Otaki
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Foglesong
authors.forename: Philip F
authors.initials: PF
authors.lastname: Hughes
authors.forename: Shelley
authors.initials: S
authors.lastname: Turkington
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Kanda
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000818:Animals; D002417:Cattle; D002851:Chromatography, High Pressure Liquid; D020650:Combinatorial Chemistry Techniques; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051231:Farnesyltranstransferase; D006801:Humans; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D018631:ras Proteins / Q000378:metabolism
chemical_list: C475431:4-(2-bromophenyl)-2-(3,4-dihydroxyphenyl)-3-nitro-1-(3-pyridylmethyl)piperidine; D004791:Enzyme Inhibitors; D010880:Piperidines; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase; D018631:ras Proteins