6-Position optimization of tricyclic 4-quinolone-based inhibitors of glycogen synthase kinase-3ß: discovery of nitrile derivatives with picomolar potency.

ABSTRACT

We previously disclosed tricylic, 6-carboxylic acid-bearing 4-quinolones as GSK-3ß inhibitors. Herein we discuss the optimization of this series to yield a series of more potent 6-nitrile analogs with insignificant anti-microbial activity. Finally, kinase profiling indicated that members of this class were highly specific GSK-3 inhibitors.