Inhibition of the soluble epoxide hydrolase (sEH) is a promising new therapeutic approach in the treatment of inflammation. Driven by the in-house database product lead 1, a hybridization strategy was utilized for the design of a series of novel benzo[d]thiazol derivatives. To our delight, D016, a byproduct of compound 9, was obtained with an extraordinarily low IC₅₀ value of 0.1 nM but poor physical and chemical properties. After removal of a non-essential urea moiety or replacement of the urea group by an amide group, compounds 15a, 17p, and 18d were identified as promising sEH inhibitors, and their molecular binding modes to sEH were constructed. Furthermore, compounds 15a and 18d exhibited more effective in vivo anti-inflammatory effect than t-AUCB in carrageenan-induced mouse paw edema. Compound 15a also showed moderate metabolic stability with a half-time of 34.7 min. Although 18d was unstable in rat liver microsomes, it might be a “prodrug”. In conclusion, this study could provide valuable insights into discovery of new sEH inhibitors, and compounds 15a and 18d were worthy of further development as potential drug candidates to treat inflammation.

可溶性环氧化物水解酶（sEH）的抑制是一种有希望的新型治疗炎症的方法。在内部数据库产品Lead 1的驱动下，采用杂交策略设计了一系列新型苯并[ d ]噻唑衍生物。令我们高兴的是，获得了化合物9的副产物D016，其IC ₅₀值极低，仅为0.1 nM，但理化性能却很差。在除去非必要的脲部分或用酰胺基团取代脲基之后，化合物15a，17p和18d被鉴定为有希望的sEH抑制剂，并构建了它们与sEH的分子结合模式。此外，在角叉菜胶诱导的小鼠爪水肿中，化合物15a和18d显示出比t -AUCB更有效的体内抗炎作用。化合物15a还显示出中等的代谢稳定性，半衰期为34.7分钟。尽管18d在大鼠肝微粒体中不稳定，但它可能是“前药”。总之，这项研究可以为发现新的sEH抑制剂提供有价值的见解，并且化合物15a和18d作为治疗炎症的潜在候选药物值得进一步开发。