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 IC₅₀ 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.

微粒体环氧水解酶（mEH）水解多种含环氧化物的分子。尽管涉及异源生物的代谢，但最近的研究将mEH与某些疾病状况的发作和发展相关。该现象部分归因于mEH在水解内源性脂质介体中起的重要作用，表明其更为复杂和广泛的生理功能。为了获得进一步研究该酶靶标的生物学和治疗潜力的药理学工具，我们描述了具有IC ₅₀的人mEH的高效2-烷硫基乙酰胺抑制剂的开发值在低纳摩尔范围内。与以前获得的伯胺，酰胺和尿素基mEH抑制剂相比，它们的效力高约2个数量级。实验测定结果和通过抑制剂与mEH同源模型的对接计算确定的结合合理性表明，连接至烷基侧链的酰胺和苄基硫基作为关键药效基团。