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 p38α mitogen-activated protein kinase and glycogen synthase kinase 3β (GSK3β). 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) (p38α, IC50 = 16 nM; GSK3β, IC50 = 35 nM) featuring an excellent metabolic stability and an appreciable isoform selectivity over the closely related GSK3α. Our findings were rationalized by computational docking studies based on previously published X-ray structures.
Keywords: Alzheimer's disease; Dual inhibitors; Glycogen synthase kinase 3β; Kinase inhibitors; Pyridinylimidazoles; p38α MAP kinase.
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