优化 N-苄基苯并恶唑-2-酮作为巨噬细胞移动抑制因子（MIF）的受体拮抗剂。
Optimization of N-benzyl-benzoxazol-2-ones as receptor antagonists of macrophage migration inhibitory factor (MIF).
机构信息
Department of Chemistry, Yale University, New Haven, CT 06520-8107, USA.
出版信息
Bioorg Med Chem Lett. 2010 Oct 1;20(19):5811-4. doi: 10.1016/j.bmcl.2010.07.129. Epub 2010 Aug 3.
Abstract
The cytokine MIF is involved in inflammation and cell proliferation via pathways initiated by its binding to the transmembrane receptor CD74. MIF also exhibits keto-enol tautomerase activity, believed to be vestigial in mammals. Starting from a 1 μM hit from virtual screening, substituted benzoxazol-2-ones have been discovered as antagonists with IC(50) values as low as 7.5 nM in a tautomerase assay and 80 nM in a MIF-CD74 binding assay. Additional studies for one of the potent inhibitors demonstrated that it is not a covalent inhibitor of MIF and that it attenuates MIF-dependent ERK1/2 phosphorylation in human synovial fibroblasts.
摘要
细胞因子 MIF 通过其与跨膜受体 CD74 结合所引发的途径参与炎症和细胞增殖。MIF 还表现出酮-烯醇互变异构酶活性，这种活性在哺乳动物中被认为是残余的。从虚拟筛选的 1 μM 命中物开始，已经发现取代的苯并恶唑-2-酮作为拮抗剂，在互变异构酶测定中 IC(50)值低至 7.5 nM，在 MIF-CD74 结合测定中 IC(50)值低至 80 nM。对一种强效抑制剂的进一步研究表明，它不是 MIF 的共价抑制剂，并且它可以减弱人滑膜成纤维细胞中 MIF 依赖性 ERK1/2 磷酸化。
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