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 p38α mitogen-activated protein kinase and glycogen synthase kinase 3β (GSK3β). Both enzymes are potential therapeutic targets for neurodegenerative disorders, like Alzheimer's disease.

From 2-Alkylsulfanylimidazoles to 2-Alkylimidazoles: An Approach towards Metabolically More Stable p38α MAP Kinase Inhibitors.

In vitro and in vivo metabolism studies revealed that 2-alkylsulfanylimidazole (4-(5-(4-fluorophenyl)-2-(methylthio)-1-imidazol-4-yl)--(1-phenylethyl)pyridin-2-amine) undergoes rapid oxidation to the sulfoxide. Replacing the sulfur atom present in the two potent p38α mitogen-activated protein (MAP) kinase inhibitors and (2-((5-(4-fluorophenyl)-4-(2-((3-methylbutan-2-yl)amino)pyridin-4-yl)-1-imidazol-2-yl)thio)ethan-1-ol) by a methylene group resulted in 2-alkylimidazole derivatives and , respectively, having a remarkably improved metabolic stability. The 2-alkylimidazole analogs and showed 20% and 10% biotransformation after 4 h of incubation with human liver microsomes, respectively.