title: Synthesis and biological evaluation of p38alpha kinase-targeting dialkynylimidazoles.
abstract: 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.
authors.affiliation: Division of Medicinal Chemistry, College of Pharmacy, The University of Texas at Austin, Austin, TX, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.forename: Tamer S
authors.initials: TS
authors.lastname: Kaoud
authors.forename: Christophe
authors.initials: C
authors.lastname: Laroche
authors.forename: Kevin N
authors.initials: KN
authors.lastname: Dalby
authors.forename: Sean M
authors.initials: SM
authors.lastname: Kerwin
mesh_terms: D000494:Allosteric Regulation; D018360:Crystallography, X-Ray; D015195:Drug Design; D007093:Imidazoles / Q000737:chemistry / Q000378:metabolism*; D048308:Mitogen-Activated Protein Kinase 14 / Q000378:metabolism; D008956:Models, Chemical; D016328:NF-kappa B / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D013379:Substrate Specificity; D048051:p38 Mitogen-Activated Protein Kinases / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology
chemical_list: D007093:Imidazoles; D016328:NF-kappa B; D047428:Protein Kinase Inhibitors; D048308:Mitogen-Activated Protein Kinase 14; D048051:p38 Mitogen-Activated Protein Kinases