Department of Pharmaceutical Chemistry, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
Mini Rev Med Chem. 2023;23(1):99-117. doi: 10.2174/1389557522666220531152812.
Soluble epoxide hydrolase is a class of α/β-fold hydrolase enzymes that exist in numerous organs and tissues, including the liver, kidney, brain, and vasculature. This homodimer enzyme is responsible for degrading epoxyeicosatrienoic acids to the less active vicinal diols, dihydroxyeicosatrienoic acids by adding a molecule of water to an epoxide in the cytochrome P450 pathway. Soluble epoxide hydrolase was firstly assayed and characterized by Hammock and colleagues about 40 years ago. Upholding high epoxyeicosatrienoic acid blood levels by inhibiting soluble epoxide hydrolase has been proposed as a hopeful strategy to treat renal and cardiovascular diseases, inflammation, and pain. Therefore, developing novel soluble epoxide hydrolase inhibitors has been an attractive research topic for many years. Regarding this issue, some carbamates, heterocycles, amides, and ureas have been proposed; however, rapid metabolism, low solubility, high melting point, and weak pharmacokinetic characteristics are challenges posed to the researchers. In this review, we have focused on the role of the soluble epoxide hydrolase in the metabolic pathway of arachidonic acid, and categorized the most representative soluble epoxide hydrolase inhibitors into two main classes of synthetic and natural compounds. The structures have been evaluated and an exemplary structure-activity relationship has been provided for further development of potent inhibitors at the end. According to our findings, urea-based inhibitors were preferred to the amide-based scaffolds due to the better fitting into the active site. An aromatic linker is a suitable bridge to connect primary and secondary pharmacophores compared with aliphatic linkers.
可溶性环氧化物水解酶是一类 α/β 折叠水解酶，存在于许多器官和组织中，包括肝脏、肾脏、大脑和血管。这种同二聚体酶负责通过在细胞色素 P450 途径中将水分子添加到环氧化物中来将环氧二十碳三烯酸降解为活性较低的顺式二醇、二羟二十碳三烯酸。可溶性环氧化物水解酶最初是由 Hammock 及其同事在大约 40 年前测定和表征的。通过抑制可溶性环氧化物水解酶来维持高环氧二十碳三烯酸的血液水平，已被提议作为治疗肾脏和心血管疾病、炎症和疼痛的有希望的策略。因此，开发新型可溶性环氧化物水解酶抑制剂多年来一直是一个有吸引力的研究课题。关于这个问题，已经提出了一些氨基甲酸酯、杂环、酰胺和脲类；然而，快速代谢、低溶解度、高熔点和弱药代动力学特性是研究人员面临的挑战。在这篇综述中，我们重点关注了可溶性环氧化物水解酶在花生四烯酸代谢途径中的作用，并将最具代表性的可溶性环氧化物水解酶抑制剂分为合成和天然化合物两大类。最后，对结构进行了评估，并提供了一个典型的结构-活性关系，以进一步开发有效的抑制剂。根据我们的研究结果，与酰胺基支架相比，基于脲的抑制剂由于更好地适应活性部位而受到青睐。与脂肪族连接子相比，芳香族连接子是连接初级和次级药效团的合适桥接。
