Bioorganic & Medicinal Chemistry Letters 2004-06-21

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

Index: Bioorg. Med. Chem. Lett. 14 , 3245-3250, (2004)

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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.