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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.

SUBMITTER: Li J

PROVIDER: S-EPMC2789032 | biostudies-literature | 2009 Nov

REPOSITORIES: biostudies-literature

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Synthesis and biological evaluation of p38alpha kinase-targeting dialkynylimidazoles.

Li Jing J Kaoud Tamer S TS Laroche Christophe C Dalby Kevin N KN Kerwin Sean M SM

Bioorganic & medicinal chemistry letters 20090927 22

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 ...[more]

PMID: 19822424

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