title: 2-(6-Phenyl-1H-indazol-3-yl)-1H-benzo[d]imidazoles: design and synthesis of a potent and isoform selective PKC-zeta inhibitor.
abstract: The inhibition of PKC-zeta has been proposed to be a potential drug target for immune and inflammatory diseases. A series of 2-(6-phenyl-1H indazol-3-yl)-1H-benzo[d]imidazoles with initial high crossover to CDK-2 has been optimized to afford potent and selective inhibitors of protein kinase c-zeta (PKC-zeta). The determination of the crystal structures of key inhibitor:CDK-2 complexes informed the design and analysis of the series. The most selective and potent analog was identified by variation of the aryl substituent at the 6-position of the indazole template to give a 4-NH(2) derivative. The analog displays good selectivity over other PKC isoforms (alpha, betaII, gamma, delta, epsilon, mu, theta, eta and iota/lambda) and CDK-2, however it displays marginal selectivity against a panel of other kinases (37 profiled).
authors.affiliation: Department of Medicinal Chemistry, Pfizer Global Research and Development, 700 Chesterfield Pkwy, AA236, Chesterfield, MO 63017, USA. john.i.trujillo@pfizer.com
authors.forename: John I
authors.initials: JI
authors.lastname: Trujillo
authors.forename: James R
authors.initials: JR
authors.lastname: Kiefer
authors.forename: Wei
authors.initials: W
authors.lastname: Huang
authors.forename: Atli
authors.initials: A
authors.lastname: Thorarensen
authors.forename: Li
authors.initials: L
authors.lastname: Xing
authors.forename: Nicole L
authors.initials: NL
authors.lastname: Caspers
authors.forename: Jacqueline E
authors.initials: JE
authors.lastname: Day
authors.forename: Karl J
authors.initials: KJ
authors.lastname: Mathis
authors.forename: Kuniko K
authors.initials: KK
authors.lastname: Kretzmer
authors.forename: Beverley A
authors.initials: BA
authors.lastname: Reitz
authors.forename: Robin A
authors.initials: RA
authors.lastname: Weinberg
authors.forename: Roderick A
authors.initials: RA
authors.lastname: Stegeman
authors.forename: Ann
authors.initials: A
authors.lastname: Wrightstone
authors.forename: Lori
authors.initials: L
authors.lastname: Christine
authors.forename: Robert
authors.initials: R
authors.lastname: Compton
authors.forename: Xiong
authors.initials: X
authors.lastname: Li
mesh_terms: D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D018360:Crystallography, X-Ray; D019925:Cyclin A / Q000737:chemistry; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D008956:Models, Chemical; D008958:Models, Molecular; D008968:Molecular Conformation; D020033:Protein Isoforms; D011493:Protein Kinase C / Q000737:chemistry* / Q000302:isolation & purification*; D000099221:Protein Kinase C zeta
chemical_list: D001562:Benzimidazoles; D019925:Cyclin A; D051357:Cyclin-Dependent Kinase 2; D004791:Enzyme Inhibitors; D007093:Imidazoles; D020033:Protein Isoforms; D011493:Protein Kinase C; D000099221:Protein Kinase C zeta; C031000:benzimidazole