title: 3-(7-Azaindolyl)-4-arylmaleimides as potent, selective inhibitors of glycogen synthase kinase-3.
abstract: A novel series of acyclic 3-(7-azaindolyl)-4-(aryl/heteroaryl)maleimides was synthesized and evaluated for activity against GSK-3beta and selectivity versus PKC-betaII, as well as a broad panel of protein kinases. Compounds 14 and 17c potently inhibited GSK-3beta (IC(50)=7 and 26 nM, respectively) and exhibited excellent selectivity over PKC-betaII (325 and >385-fold, respectively). Compound 17c was also highly selective against 68 other protein kinases. In a cell-based functional assay, both 14 and 17c effectively increased glycogen synthase activity by inhibiting GSK-3beta.
authors.affiliation: Drug Discovery, Johnson & Johnson Pharmaceutical Research & Development, Spring House, PA 19477-0776, USA. hzhang@prdus.jnj.com
authors.forename: Han-Cheng
authors.initials: HC
authors.lastname: Zhang
authors.forename: Hong
authors.initials: H
authors.lastname: Ye
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Conway
authors.forename: Claudia K
authors.initials: CK
authors.lastname: Derian
authors.forename: Michael F
authors.initials: MF
authors.lastname: Addo
authors.forename: Gee-Hong
authors.initials: GH
authors.lastname: Kuo
authors.forename: Leonard R
authors.initials: LR
authors.lastname: Hecker
authors.forename: Diane R
authors.initials: DR
authors.lastname: Croll
authors.forename: Jian
authors.initials: J
authors.lastname: Li
authors.forename: Lori
authors.initials: L
authors.lastname: Westover
authors.forename: Jun Z
authors.initials: JZ
authors.lastname: Xu
authors.forename: Richard
authors.initials: R
authors.lastname: Look
authors.forename: Keith T
authors.initials: KT
authors.lastname: Demarest
authors.forename: Patricia
authors.initials: P
authors.lastname: Andrade-Gordon
authors.forename: Bruce P
authors.initials: BP
authors.lastname: Damiano
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Maryanoff
mesh_terms: D002460:Cell Line; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008301:Maleimides / Q000737:chemistry* / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D008301:Maleimides; D047428:Protein Kinase Inhibitors; D038362:Glycogen Synthase Kinase 3