Pyridinylimidazoles As Gsk3 Beta Inhibitors: The Impact Of Tautomerism On Compound Activity Via Water Networks

Glycogen synthase kinase-3 beta (GSK3 beta) is involved in many pathological conditions and represents an attractive drug target. We previously reported dual GSK3 beta/p38 alpha mitogen-activated protein kinase inhibitors and identified N-(4-(4-(4-fluorophenyl)-2-methyl-1H-imidazol-5-yl)pyridin-2-yl)cyclopropanecarboxamide (1) as a potent dual inhibitor of both target kinases. In this study, we aimed to design selective GSK3 beta inhibitors based on our pyridinylimidazole scaffold. Our efforts resulted in several novel and potent GSK3 beta inhibitors with IC50 values in the low nanomolar range. 5-(2-(Cyclopropanecarboxamido)pyridin-4-yl)-4-cyclopropyl-1H-imidazole-2-carboxamide (6g) displayed very good kinase selectivity as well as metabolical stability and inhibited GSK3 beta activity in neuronal SH-SY5Y cells. Interestingly, we observed the importance of the 2-methylimidazole's tautomeric state for the compound activity. Finally, we reveal how this crucial tautomerism effect is surmounted by imidazole-2-carboxamides, which are able to stabilize the binding via enhanced water network interactions, regardless of their tautomeric state.