Design, synthesis and biological evaluation of novel imidazopyridines as potential antidiabetic GSK3β inhibitors

Design, synthesis and biological evaluation of the imidazopyridine analogs as novel GSK3 beta inhibitors for treatment of type 2 diabetes mellitus are described. Most of the analogs exhibited excellent inhibitory activities (IC50 < 44 nM) against glycogen synthase kinase 3b (GSK3 beta). The structure-activity relationship (SAR) of the imidazopyridine analogs and the binding mode of analog 23 in the catalytic domain of GSK3 beta, based on our X-ray crystallography study, are described. In particular, analog 28, which was selected as a potential drug candidate for treatment of type 2 diabetes mellitus, exhibited excellent GSK3 beta inhibition, pharmacokinetic profiles and blood glucose lowering effect in mouse. (C) 2012 Elsevier Ltd. All rights reserved.