title: Enhanced FTase activity achieved via piperazine interaction with catalytic zinc.
abstract: Benzocycloheptapyridine tricyclic compounds with piperazine or substituted piperidine moieties extending either from the 5- or 6-position of the tricyclic bridgehead exhibited enhanced FTase activity: this resulted from favorable binding of the ligand nitrogen with the catalytic zinc found in the FTase. A single isomer at C-11 with piperazine adduct extending from the 6-position, compound 24, exhibited excellent FTase activity with IC50 = 0.007 microM, soft agar IC50 = 72 nM, and Rat AUC(PO, 10 mpk) = 4.0 microM x h. X-ray of (-)-[8-chloro-6-(1-piperazinyl)-1H-benzo[5,6]]cyclohepta[1,2-b]pyridine-11-yl]-1-(methylsulfonyl)piperidine 24 bound to Ftase revealed favorable interaction between piperazine nitrogen and catalytic zinc atom.
authors.affiliation: Schering-Plough Research Institute, 2015 Galloping Hill Road, K-15-3-3545, Kenilworth, NJ 07033, USA. george.njoroge@spcorp.com
authors.forename: F George
authors.initials: FG
authors.lastname: Njoroge
authors.forename: Bancha
authors.initials: B
authors.lastname: Vibulbhan
authors.forename: Patrick
authors.initials: P
authors.lastname: Pinto
authors.forename: Corey
authors.initials: C
authors.lastname: Strickland
authors.forename: W Robert
authors.initials: WR
authors.lastname: Bishop
authors.forename: Amin
authors.initials: A
authors.lastname: Nomeir
authors.forename: Vivyoor
authors.initials: V
authors.lastname: Girijavallabhan
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors / Q000737:chemistry*; D001665:Binding Sites / Q000187:drug effects; D002384:Catalysis / Q000187:drug effects; D018360:Crystallography, X-Ray; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000737:chemistry* / Q000494:pharmacology; D000077489:Piperazine; D010879:Piperazines / Q000737:chemistry*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D015032:Zinc / Q000737:chemistry*
chemical_list: D008024:Ligands; D009942:Organometallic Compounds; D010879:Piperazines; D000077489:Piperazine; D019883:Alkyl and Aryl Transferases; C064911:p21(ras) farnesyl-protein transferase; D015032:Zinc