Department of Entomology and Nematology, UCD Comprehensive Cancer Center, University of California Davis, Davis, CA, 95616, United States.
Department of Chemistry, University of California Davis, Davis, CA, 95616, United States.
Eur J Med Chem. 2020 May 1;193:112206. doi: 10.1016/j.ejmech.2020.112206. Epub 2020 Mar 13.
Microsomal epoxide hydrolase (mEH) hydrolyzes a wide range of epoxide containing molecules. Although involved in the metabolism of xenobiotics, recent studies associate mEH with the onset and development of certain disease conditions. This phenomenon is partially attributed to the significant role mEH plays in hydrolyzing endogenous lipid mediators, suggesting more complex and extensive physiological functions. In order to obtain pharmacological tools to further study the biology and therapeutic potential of this enzyme target, we describe the development of highly potent 2-alkylthio acetamide inhibitors of the human mEH with IC values in the low nanomolar range. These are around 2 orders of magnitude more potent than previously obtained primary amine, amide and urea-based mEH inhibitors. Experimental assay results and rationalization of binding through docking calculations of inhibitors to a mEH homology model indicate that an amide connected to an alkyl side chain and a benzyl-thio function as key pharmacophore units.
微粒体环氧化物水解酶（mEH）可水解多种含环氧化物的分子。尽管它参与了外来物质的代谢，但最近的研究将 mEH 与某些疾病的发生和发展联系起来。这种现象部分归因于 mEH 在水解内源性脂质介质方面的重要作用，这表明它具有更复杂和广泛的生理功能。为了获得药理学工具来进一步研究该酶靶标的生物学和治疗潜力，我们描述了具有低纳摩尔范围内的 IC 值的人 mEH 的高活性 2-烷基硫代乙酰胺抑制剂的开发。这些抑制剂的活性比以前获得的基于伯胺、酰胺和脲的 mEH 抑制剂高 2 个数量级。通过将抑制剂对接至 mEH 同源模型进行实验测定结果和结合的合理化，表明酰胺连接到烷基侧链和苄基-硫基作为关键药效团单元。
