paullone and Disease-Models--Animal

Here we report on the discovery of a series of maleimides which have high potency and good selectivity for GSK-3beta. The incorporation of polar groups afforded compounds with good bioavailability. The most potent compound 34 has an IC(50) of 0.6nM for GSK-3beta, over 100-fold selectivity against a panel of other kinases, and shows efficacy in rat osteoporosis models. The X-ray structure of GSK-3beta protein with 34 bound revealed the binding mode of the template and provided insights for future optimization opportunities.

Topics: Administration, Oral; Animals; Binding Sites; Crystallography, X-Ray; Disease Models, Animal; Drug Discovery; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Indoles; Maleimides; Mice; Protein Kinase C; Protein Kinase Inhibitors; Rats; Structure-Activity Relationship