Discovery of potent and bioavailable GSK-3β inhibitors

Here we report on the discovery of a series of maleimides which have high potency and good selectivity for GSK-3β. The incorporation of polar groups afforded compounds with good bioavailability. The most potent compound 34 has an IC₅₀ of 0.6 nM for GSK-3β, over 100-fold selectivity against a panel of other kinases, and shows efficacy in rat osteoporosis models. The X-ray structure of GSK-3β protein with 34 bound revealed the binding mode of the template and provided insights for future optimization opportunities.