Synthesis and biological evaluation of 3-benzisoxazolyl-4-indolylmaleimides as potent, selective inhibitors of glycogen synthase kinase-3β.

A series of novel 3-benzisoxazolyl-4-indolyl-maleimides were synthesized and evaluated for their GSK-3 beta inhibitory activity. Most compounds exhibited high inhibitory potency towards GSK-3 beta. Among them, compound 7j with an IC50 value of 0.73 nM was the most promising GSK-3 beta inhibitor. Preliminary structure-activity relationships were examined and showed that different substituents on the indole ring and N-1-position of the indole ring had varying degrees of influence on the GSK-3 beta inhibitory potency. Compounds 7c, 7f, 7j-l and 7o-q could obviously reduce A beta-induced Tau hyperphosphorylation by inhibiting GSK-3 beta in a cell-based functional assay.