Synthesis and biological evaluation of p38alpha kinase-targeting dialkynylimidazoles

Based on the mild, thermal rearrangement of 1,2-dialkynylimidazoles to reactive carbene or diradical intermediates, a series of 1,2-dialkynylimidazoles were designed as potential irreversible p38 MAP kinase alpha-isoform (p38alpha) inhibitors. The synthesis of these dialkynylimidazoles and their kinase inhibition activity is reported. The 1-ethynyl-substituted dialkynylimidazole 14 is a potent (IC(50)=200 nM) and selective inhibitor of p38alpha. Moreover, compound 14 covalently modifies p38alpha as determined by ESI-MS after 12h incubation at 37 degrees C. The unique kinase inhibition, covalent kinase adduct formation, and minimal CYP450 2D6 inhibition by compound 14 demonstrate that dialkynylimidazoles are a new, promising class of p38alpha inhibitors.