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-3β and selectivity versus PKC-βII, as well as a broad panel of protein kinases. Compounds 14 and 17c potently inhibited GSK-3β (IC 50 =7 and 26 nM, respectively) and exhibited excellent selectivity over PKC-βII (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-3β.