Pyridinylimidazoles as GSK3β Inhibitors: The Impact of Tautomerism on Compound Activity via Water Networks.

ABSTRACT: Glycogen synthase kinase-3β (GSK3β) is involved in many pathological conditions and represents an attractive drug target. We previously reported dual GSK3β/p38α 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 GSK3β inhibitors based on our pyridinylimidazole scaffold. Our efforts resulted in several novel and potent GSK3β 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 G

SUBMITTER: Heider F 

PROVIDER: S-EPMC6792175 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature