Synthesis and biological evaluation of 3,6-diamino-1H-pyrazolo[3,4-b]pyridine derivatives as protein kinase inhibitors

The synthesis and biological evaluation of a number of differently substituted 3,6-diamino-1H-pyrazolo[3,4-b]pyridine derivatives are reported. From the inhibition results on a selection of disease-relevant protein kinases [IC50 (μM) DYRK1A = 11; CDK5 = 0.41; GSK-3 = 1.5] we have observed that 3,6-diamino-4-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile (4) constitutes a potential new and simple lead compound in the search of drugs for the treatment of Alzheimer’s disease.

A docking analysis of 3,6-diamino-4-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile (4) [IC50 (μM) DYRK1A = 11; CDK5 = 0.41; GSK-3 = 1.5] suggests that he amino substituent at the pyridine ring of compound 4 drives the binding mode as it forms two hydrogen bonds with the backbone CO of Asp133. This allows the pyridinic N and NH group of the pyrazolic ring to establish two hydrogen bonds with the backbone NH and carbonyl of Val135.Figure optionsDownload as PowerPoint slide