3-(7-Azaindolyl)-4-arylmaleimides as potent, selective inhibitors of glycogen synthase kinase-3
作者: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
日期:2004.6
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 (IC50=7 and 26nM, 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. (C) 2004 Elsevier Ltd. All rights reserved.