Discovery of potent and bioavailable GSK-3@b inhibitors

Bioorg Med Chem Lett 20(5):4 (2010) PMID 20138512

Here we report on the discovery of a series of maleimides which have high potency and good selectivity for GSK-3@b. The incorporation of polar groups afforded compounds with good bioavailability. The most potent compound 34 has an IC"5"0 of 0.6nM for GSK-3@b, over 100-fold selectivity against a panel of other kinases, and shows efficacy in rat osteoporosis models. The X-ray structure of GSK-3@b protein with 34 bound revealed the binding mode of the template and provided insights for future optimization opportunities.