Inhibitors of Glycogen Synthase Kinase 3� (GSK3�), a serine/threonine protein kinase, offer promise as therapeutic agents to treat GSK-3� mediated diseases such as diabetes, Alzheimer's disease, and various CNS disorders.  We previously disclosed tricylic, 6-carboxylic acid-bearing 4-quinolones as GSK-3� inhibitors. Herein we discuss the optimization of this series to yield a series of more potent 6-nitrile analogs (e.g., AX9839) with insignificant anti-microbial activity. Finally, KiNativ� kinase profiling indicated that members of this class were highly specific GSK-3 inhibitors.

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

243rd National Meeting (2012)

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