Pyridinylimidazoles as dual glycogen synthase kinase 3β/p38α mitogen-activated protein kinase inhibitors

Compounds simultaneously inhibiting two targets that are involved in the progression of the same complex disease may exhibit additive or even synergistic therapeutic effects. Here we unveil 2,4,5-trisubstituted imidazoles as dual inhibitors of p38 alpha mitogen-activated protein kinase and glycogen synthase kinase 3 beta (GSK3 beta). Both enzymes are potential therapeutic targets for neurodegenerative disorders, like Alzheimer's disease. A set of 39 compounds was synthesized and evaluated in kinase activity assays for their ability to inhibit both target kinases. Among the synthesized compounds, potent dual-target-directed inhibitors showing IC50 values down to the low double-digit nanomolar range, were identified. One of the best balanced dual inhibitors presented in here is N-(4-(2-ethyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)pyridin-2-yl)cyclopropanecarboxamide (20c) (p38 alpha, IC50 = 16 nM; GSK3 beta, IC50 = 35 nM) featuring an excellent metabolic stability and an appreciable isoform selectivity over the closely related GSK3 alpha. Our findings were rationalized by computational docking studies based on previously published X-ray structures. (C) 2019 Elsevier Masson SAS. All rights reserved.