Hejazi Leila, Rezaee Elham, Tabatabai Sayyed Abbas
Department of Pharmaceutical Chemistry, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
Iran J Pharm Res. 2019 Fall;18(4):1759-1769. doi: 10.22037/ijpr.2019.112047.13500.
Soluble epoxide hydrolase enzyme is a promising therapeutic target for hypertension, vascular inflammation, pain and some other risk factors of cardiovascular diseases. The most potent sEH inhibitors reported in the literature are urea-based ones which often have poor bioavailability. In this study, in a quest for finding potent inhibitors of soluble epoxide hydrolase, some 4,6-disubstituted pyridin-2(1)-one derivatives were designed and synthesized. The designed compounds fit properly in the active site pocket of this enzyme in docking studies and have appropriate distances for effective hydrogen binding to important amino acids Tyr383, Tyr466, and Asp335. The results of biological evaluation of these compounds against soluble epoxide hydrolase enzyme indicate most compounds have acceptable inhibitory activity and compound is the most potent inhibitor with inhibitory activity of 86%.
可溶性环氧化物水解酶是治疗高血压、血管炎症、疼痛及心血管疾病其他一些危险因素的一个有前景的治疗靶点。文献报道的最有效的可溶性环氧化物水解酶抑制剂是基于尿素的抑制剂，其生物利用度往往较差。在本研究中，为寻找可溶性环氧化物水解酶的有效抑制剂，设计并合成了一些4,6-二取代吡啶-2(1)-酮衍生物。在对接研究中，设计的化合物能很好地契合该酶的活性位点口袋，并且与重要氨基酸Tyr383、Tyr466和Asp335形成有效氢键的距离合适。这些化合物针对可溶性环氧化物水解酶的生物学评价结果表明，大多数化合物具有可接受的抑制活性，化合物 是最有效的抑制剂，抑制活性为86%。
