title: Macrocyclic piperazinones as potent dual inhibitors of farnesyltransferase and geranylgeranyltransferase-I.
abstract: A series of macrocyclic piperazinone compounds with dual farnesyltransferase/geranylgeranyltransferase-I inhibitory activity was prepared. These compounds were found to be potent inhibitors of protein prenylation in cell culture. A hypothesis for the binding mode of compound 3o in FPTase is proposed.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA. christopher_dinsmore@merck.com
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Dinsmore
authors.forename: C Blair
authors.initials: CB
authors.lastname: Zartman
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Bergman
authors.forename: Marc T
authors.initials: MT
authors.lastname: Abrams
authors.forename: Carolyn A
authors.initials: CA
authors.lastname: Buser
authors.forename: J Christopher
authors.initials: JC
authors.lastname: Culberson
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Davide
authors.forename: Michelle
authors.initials: M
authors.lastname: Ellis-Hutchings
authors.forename: Christine
authors.initials: C
authors.lastname: Fernandes
authors.forename: Samuel L
authors.initials: SL
authors.lastname: Graham
authors.forename: George D
authors.initials: GD
authors.lastname: Hartman
authors.forename: Hans E
authors.initials: HE
authors.lastname: Huber
authors.forename: Robert B
authors.initials: RB
authors.lastname: Lobell
authors.forename: Scott D
authors.initials: SD
authors.lastname: Mosser
authors.forename: Ronald G
authors.initials: RG
authors.lastname: Robinson
authors.forename: Theresa M
authors.initials: TM
authors.lastname: Williams
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006571:Heterocyclic Compounds / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology*; D017368:Protein Prenylation; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured / Q000187:drug effects* / Q000201:enzymology
chemical_list: D004791:Enzyme Inhibitors; D006571:Heterocyclic Compounds; D010879:Piperazines; D019883:Alkyl and Aryl Transferases; C083291:geranylgeranyltransferase type-I; C064911:p21(ras) farnesyl-protein transferase