Design, synthesis and structure-activity relationships of 1,3,4-oxadiazole derivatives as novel inhibitors of glycogen synthase kinase-3β

Glycogen synthase kinase-3 beta (GSK-3 beta) is implicated in abnormal hyperphosphorylation of tau protein and its inhibitors are expected to be a promising therapeutic agents for the treatment of Alzheimer's disease. Here we report design, synthesis and structure-activity relationships of a novel series of oxadiazole derivatives as GSK-3 beta inhibitors. Among these inhibitors, compound 20x showed highly selective and potent GSK-3 beta inhibitory activity in vitro and its binding mode was determined by obtaining the X-ray co-crystal structure of 20x and GSK-3 beta. (C) 2009 Elsevier Ltd. All rights reserved.