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

Abstract

In vitro and in vivo metabolism studies revealed that 2-alkylsulfanylimidazole <b>ML3403</b> (4-(5-(4-fluorophenyl)-2-(methylthio)-1<i>H</i>-imidazol-4-yl)-<i>N</i>-(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 <b>ML3403</b> and <b>LN950</b> (2-((5-(4-fluorophenyl)-4-(2-((3-methylbutan-2-yl)amino)pyridin-4-yl)-1<i>H</i>-imidazol-2-yl)thio)ethan-1-ol) by a methylene group resulted in 2-alkylimidazole derivatives <b>1</b> and <b>2</b>, respectively, having a remarkably improved metabolic stability. The 2-alkylimidazole analogs <b>1</b> and <b>2</b> showed 20% and 10% biotransformation after 4 h of incubation with human liver microsomes, respectively. They display a 4-fold increased binding affinity towards the target kinase as well as similar in vitro potency and ex vivo efficacy relative to their 2-alkylsulfanylimidazole counterparts <b>ML3403</b> and <b>LN950</b>. For example, 2-alkylimidazole <b>2</b>, the analog of <b>LN950</b>, inhibits both the p38α MAP kinase as well as the LPS-stimulated tumor necrosis factor-α release from human whole blood in the low double-digit nanomolar range.