Glycogen synthase kinase-3 (GSK-3) has been proposed to play a crucial role in the pathogenesis of many diseases including cancer, stroke, bipolar disorders, diabetes and neurodegenerative diseases.  GSK-3 inhibition has been a major area of pharmaceutical interest over the last two decades. A plethora of reports appeared recently on selective inhibitors and their co-crystal structures in GSK-3�. We identified several series of promising new GSK-3� inhibitors from a coherent design around a pyrrolopyridinone core structure. A systematic exploration of the chemical space around the central spacer led to potent single digit and sub-nanomolar GSK-3� inhibitors. An exemplary compound from one series showed significant pTau lowering in a transgenic AD mouse model. X-ray crystallographygreatly aided in validating the binding hypotheses. The most salient features of our work including the design hypothesis, modeling studies that helped in achieving improved off-target kinase selectivity, key SAR, in vitro and in vivo, and X-ray crystallography data on select compounds will be presented.

Discovery of new acylaminopyridines as GSK-3 inhibitors by a structure guided in-depth exploration of chemical space around a pyrrolopyridinone core

247th National Meeting (2014)

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