Multi-target inhibitors have become increasing popular as a means to leverage the advantages of poly-pharmacology while simplifying drug delivery. Here, we describe dual inhibitors for soluble epoxide hydrolase (sEH) and fatty acid amide hydrolase (FAAH), two targets known to synergize when treating inflammatory and neuropathic pain. The structure activity relationship (SAR) study described herein initially started with t-TUCB (trans-4-[4-(3-trifluoromethoxyphenyl-l-ureido)-cyclohexyloxy]-benzoic acid), a potent sEH inhibitor that was previously shown to weakly inhibit FAAH. Inhibitors with a 6-fold increase of FAAH potency while maintaining high sEH potency were developed by optimization. Interestingly, compared to most FAAH inhibitors that inhibit through time-dependent covalent modification, t-TUCB and related compounds appear to inhibit FAAH through a time-independent, competitive mechanism. These inhibitors are selective for FAAH over other serine hydrolases. In addition, FAAH inhibition by t-TUCB appears to be higher in human FAAH over other species; however, the new dual sEH/FAAH inhibitors have improved cross-species potency. These dual inhibitors may be useful for future studies in understanding the therapeutic application of dual sEH/FAAH inhibition.

作为利用多药理学优势同时简化药物输送的一种手段，多靶点抑制剂已变得越来越流行。在这里，我们描述了可溶性环氧化物水解酶（sEH）和脂肪酸酰胺水解酶（FAAH）的两种抑制剂，这两种抑制剂在治疗炎症性疼痛和神经性疼痛时已知具有协同作用。本文所述的结构活性关系（SAR）研究最初始于t -TUCB（trans-4- [4-（4-（3-三氟甲氧基苯基-1-脲基）-环己氧基]-苯甲酸），一种有效的sEH抑制剂，先前已显示出弱抑制FAAH的作用。通过优化开发了在维持高sEH效能的同时，将FAAH效能提高6倍的抑制剂。有趣的是，与大多数通过时间依赖性共价修饰抑制的FAAH抑制剂相比，t -TUCB和相关化合物似乎通过时间依赖性竞争机制抑制FAAH。这些抑制剂对FAAH的选择性高于其他丝氨酸水解酶。另外，FAAH对t的抑制作用-TUCB在人类FAAH中似乎比其他物种更高；然而，新型的双重sEH / FAAH抑制剂具有更高的跨物种效价。这些双重抑制剂可能有助于将来的研究，以了解双重sEH / FAAH抑制的治疗应用。