2,5-Diaminopyrimidines and 3,5-disubstituted azapurines as inhibitors of glycogen synthase kinase-3 (GSK-3)

The discovery of two classes of pyrimidine-based inhibitors of GSK-3 is described. Optimization of these series led to inhibitors with IC50 < 10 nM and >100-fold selectivity over Aurora A kinase. A proposed binding mode of 21b is presented. One compound (33) of the pyrimidine series showed promising pharmacokinetic parameters.

Graphical abstractThe structure–activity relationships of potent and selective pyrimidine- and azapurine-based inhibitors of glycogen synthase kinase-3 (GSK-3) are reported.Figure optionsDownload full-size imageDownload as PowerPoint slide