3-(7-Azaindolyl)-4-arylmaleimides as potent, selective inhibitors of glycogen synthase kinase-3

Han-Cheng Zhang; Hong Ye; Bruce R Conway; Claudia K Derian; Michael F Addo; Gee-Hong Kuo; Leonard R Hecker; Diane R Croll; Jian Li; Lori Westover; Jun Z Xu; Richard Look; Keith T Demarest; Patricia Andrade-Gordon; Bruce P Damiano; Bruce E Maryanoff

doi:10.1016/j.bmcl.2004.03.090

3-(7-Azaindolyl)-4-arylmaleimides as potent, selective inhibitors of glycogen synthase kinase-3

Bioorg Med Chem Lett. 2004 Jun 21;14(12):3245-50. doi: 10.1016/j.bmcl.2004.03.090.

Authors

Han-Cheng Zhang¹, Hong Ye, Bruce R Conway, Claudia K Derian, Michael F Addo, Gee-Hong Kuo, Leonard R Hecker, Diane R Croll, Jian Li, Lori Westover, Jun Z Xu, Richard Look, Keith T Demarest, Patricia Andrade-Gordon, Bruce P Damiano, Bruce E Maryanoff

Affiliation

¹ Drug Discovery, Johnson & Johnson Pharmaceutical Research & Development, Spring House, PA 19477-0776, USA. [email protected]

PMID: 15149684
DOI: 10.1016/j.bmcl.2004.03.090

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.

MeSH terms

Cell Line
Glycogen Synthase Kinase 3 / antagonists & inhibitors*
Glycogen Synthase Kinase 3 / metabolism
Humans
Maleimides / chemistry*
Maleimides / pharmacology
Protein Kinase Inhibitors / chemistry*
Protein Kinase Inhibitors / pharmacology

Substances

Maleimides
Protein Kinase Inhibitors
Glycogen Synthase Kinase 3