The development of potent and selective bisarylmaleimide GSK3 inhibitors

Abstract

Many 3-aryl-4-(1,2,3,4-tetrahydro[1,4]diazepino[6,7,1- hi]indol-7-yl)maleimides exhibit potent GSK3 inhibitory activity (<100 nM IC 50), although few show significant selectivity (>100 ×) versus CDK2, CDK4, or PKCβII. However, combining 3-(imidazo[1,2- a]pyridin-3-yl), 3-(pyrazolo[1,5- a]pyridin-3-yl) or aza-analogs with a 4-(2-acyl-(1,2,3,4-tetrahydro[1,4]diazepino[6,7,1- hi]indol-7-yl)) group on the maleimide resulted in very potent inhibitors of GSK3 (⩽5 nM) with >160 to >10,000-fold selectivity versus CDK2/4 and PKCβII. These compounds also inhibited tau phosphorylation in cells and were effective in lowering plasma glucose in a rat model of type 2 diabetes (ZDF rat).