Adamantyl groups are widely used in medicinal chemistry. However, metabolism limits their usage. Herein, we report the first systematic study of adamantyl ureas and diureas bearing substituents in bridgehead positions of adamantane and/or spacers between urea groups and adamantane group, and tested their effects on soluble epoxide hydrolase inhibitor potency and metabolic stability. Interestingly, the effect on activity against human and murine sEH varied in opposite ways with each new methyl group introduced into the molecule. Compounds with three methyl substituents in adamantane were very poor inhibitors of murine sEH while still very potent against human sEH. In addition, diureas with terminal groups bigger than sEH catalytic tunnel diameter were still good inhibitors suggesting that the active site of sEH opens to capture the substrate or inhibitor molecule. The introduction of one methyl group leads to 4-fold increase in potency without noticeable loss of metabolic stability compared to the unsubstituted adamantane. However, introduction of two or three methyl groups leads to 8-fold and 98-fold decrease in stability in human liver microsomes for the corresponding compounds.

金刚烷基广泛用于药物化学中。但是，新陈代谢限制了它们的使用。在这里，我们报告了首次系统研究金刚烷脲和双脲在金刚烷桥头位置和/或脲基团与金刚烷基团之间的间隔基上带有取代基的脲，并测试了它们对可溶性环氧化物水解酶抑制剂效能和代谢稳定性的影响。有趣的是，随着分子中引入的每个新甲基，其对人和鼠sEH活性的影响以相反的方式变化。金刚烷中具有三个甲基取代基的化合物对鼠sEH的抑制作用很差，而对人sEH的抑制作用仍然很强。此外，末端基团大于sEH催化通道直径的二聚脲仍然是良好的抑制剂，表明sEH的活性位点开放以捕获底物或抑制剂分子。与未取代的金刚烷相比，一个甲基的引入导致效力增加了4倍，而没有明显的代谢稳定性损失。但是，引入两个或三个甲基会导致相应化合物在人肝微粒体中的稳定性降低8倍和98倍。