title: Design and synthesis of piperidine farnesyltransferase inhibitors with reduced glucuronidation potential.
abstract: The design and synthesis of a novel piperidine series of farnesyltransferase (FTase) inhibitors with reduced potential for metabolic glucuronidation are described. The various substitution and exchange of the phenyl group at the C-2 position of the previously described 2-(4-hydroxy)phenyl-3-nitropiperidine 1a (FTase IC(50)=5.4nM) resulted in metabolically stable compounds with potent FTase inhibition (14a IC(50)=4.3nM, 20a IC(50)=3.0nM, and 50a IC(50)=16nM). Molecular modeling studies of these compounds complexed with FTase and farnesyl pyrophosphate are also described.
authors.affiliation: Pharmaceutical Research Center, Kyowa Hakko Kogyo Co. Ltd, 1188 Shimotogari, Nagaizumi-cho, Shizuoka 411-8731, Japan.
authors.forename: Rieko
authors.initials: R
authors.lastname: Tanaka
authors.forename: Almudena
authors.initials: A
authors.lastname: Rubio
authors.forename: Nancy K
authors.initials: NK
authors.lastname: Harn
authors.forename: Douglas
authors.initials: D
authors.lastname: Gernert
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Grese
authors.forename: Jun
authors.initials: J
authors.lastname: Eishima
authors.forename: Mitsunobu
authors.initials: M
authors.lastname: Hara
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Yoda
authors.forename: Rui
authors.initials: R
authors.lastname: Ohashi
authors.forename: Takashi
authors.initials: T
authors.lastname: Kuwabara
authors.forename: Shiro
authors.initials: S
authors.lastname: Soga
authors.forename: Shiro
authors.initials: S
authors.lastname: Akinaga
authors.forename: Shinji
authors.initials: S
authors.lastname: Nara
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Kanda
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D000818:Animals; D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D020719:Glucuronides / Q000378:metabolism*; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017368:Protein Prenylation; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D020719:Glucuronides; D010880:Piperidines; D019883:Alkyl and Aryl Transferases; C064911:p21(ras) farnesyl-protein transferase