Salehi Maryam, Sedaghat Anna, Bayanati Maryam, Mahboubi Rabbani Mohammad Ismail, Rezaee Elham, Tabatabai Sayyed Abbas
Department of Pharmaceutical Chemistry, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
Chemistry Department, Loughborough University, Loughborough Leics, LE11 3TU, UK.
Mol Divers. 2025 Jul 7. doi: 10.1007/s11030-025-11267-7.
Fatty acid amide hydrolase (FAAH) enzyme, as a potential therapeutic target for the treatment of pain and inflammation, is responsible for decomposing fatty acid amides like endocannabinoids. One attractive technique for increasing the efficacy of FAAH inhibitors is to generate antinociception and anti-inflammatory effects via another route, such as soluble epoxide hydrolase (sEH) inhibition, at the same time. In this study, two series of structures bearing oxadiazole rings as dual inhibitors of FAAH/sEH were designed, synthesized, and biologically evaluated. Most compounds showed an excellent affinity towards the active sites of both enzymes compared to the standard ligands of JZL-195 and AUDA. Among all the synthesized compounds, compound 7f was a more effective inhibitor with IC values of 1.2 nM and 18 nM on FAAH and sEH enzymes, respectively. The results of the in-vitro evaluation were significantly consistent with the docking results.
脂肪酸酰胺水解酶（FAAH）作为治疗疼痛和炎症的潜在治疗靶点，负责分解内源性大麻素等脂肪酸酰胺。提高FAAH抑制剂疗效的一种有吸引力的技术是同时通过另一条途径，如抑制可溶性环氧化物水解酶（sEH），产生抗伤害感受和抗炎作用。在本研究中，设计、合成并对两个含有恶二唑环的系列结构作为FAAH/sEH双重抑制剂进行了生物学评价。与JZL-195和AUDA的标准配体相比，大多数化合物对两种酶的活性位点都表现出优异的亲和力。在所有合成化合物中，化合物7f是一种更有效的抑制剂，对FAAH和sEH酶的IC值分别为1.2 nM和18 nM。体外评价结果与对接结果显著一致。
