Division of Medicinal Chemistry, College of Pharmacy, The University of Texas at Austin, Austin, TX, USA.
Bioorg Med Chem Lett. 2009 Nov 15;19(22):6293-7. doi: 10.1016/j.bmcl.2009.09.094. Epub 2009 Sep 27.
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.
基于温和的热重排 1,2-二炔基咪唑转化为反应性卡宾或双自由基中间体，设计了一系列 1,2-二炔基咪唑作为潜在的不可逆 p38 MAP 激酶 alpha-异构体 (p38alpha) 抑制剂。报道了这些二炔基咪唑的合成及其激酶抑制活性。1-乙炔基取代的二炔基咪唑 14 是一种有效的（IC50=200 nM）和选择性的 p38alpha 抑制剂。此外，化合物 14 在 37°C 孵育 12 小时后通过 ESI-MS 确定共价修饰 p38alpha。化合物 14 的独特激酶抑制、共价激酶加合物形成和最小的 CYP450 2D6 抑制作用表明，二炔基咪唑是一类新的、有前途的 p38alpha 抑制剂。
