Kodani Sean D, Bhakta Saavan, Hwang Sung Hee, Pakhomova Svetlana, Newcomer Marcia E, Morisseau Christophe, Hammock Bruce D
Department of Entomology and Nematology, and UC Davis Comprehensive Cancer Center, University of California, Davis, Davis, CA 95616, United States.
Department of Biological Sciences, Louisiana State University, Baton Rouge, LA 70809, United States.
Bioorg Med Chem Lett. 2018 Feb 15;28(4):762-768. doi: 10.1016/j.bmcl.2018.01.003. Epub 2018 Jan 4.
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.
多靶点抑制剂作为一种利用多药理学优势同时简化药物递送的手段，越来越受到欢迎。在此，我们描述了针对可溶性环氧化物水解酶（sEH）和脂肪酸酰胺水解酶（FAAH）的双重抑制剂，这两个靶点在治疗炎症性和神经性疼痛时已知具有协同作用。本文所述的构效关系（SAR）研究最初始于反式-4-[4-(3-三氟甲氧基苯基-1-脲基)-环己氧基]-苯甲酸（t-TUCB），它是一种有效的sEH抑制剂，先前已证明其对FAAH有微弱抑制作用。通过优化开发出了对FAAH的效力提高6倍同时保持高sEH效力的抑制剂。有趣的是，与大多数通过时间依赖性共价修饰起抑制作用的FAAH抑制剂相比，t-TUCB及相关化合物似乎通过一种时间非依赖性的竞争性机制抑制FAAH。这些抑制剂对FAAH的选择性高于其他丝氨酸水解酶。此外，t-TUCB对FAAH的抑制作用在人类FAAH中似乎高于其他物种；然而，新型双重sEH/FAAH抑制剂具有更好的跨物种效力。这些双重抑制剂可能对未来理解双重sEH/FAAH抑制的治疗应用的研究有用。
