Department of Pharmaceutical Medicinal Chemistry, Faculty of Pharmacy, Al-Azhar University, Assiut, Egypt.
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Deraya University, Minia, Egypt.
Arch Pharm (Weinheim). 2022 Jul;355(7):e2200024. doi: 10.1002/ardp.202200024. Epub 2022 Apr 15.
Some cyclooxygenase (COX)-2 selective medications were withdrawn from the market just a few years after their production due to cardiovascular side effects. In this study, a new series of pyrimidine/thiazole hybrids 7a-p was synthesized as selective COX-2/soluble epoxide hydrolase (sEH) inhibitors with analgesic and anti-inflammatory effects, and lower cardiotoxicity effects. The target compounds were synthesized and in vitro tested against COX-1, COX-2, and sEH enzymes. Hybrids 7j, 7k, and 7i showed the greatest COX-2-inhibitory activity and were discovered to be the most potent dual COX-2/sEH inhibitors. In vivo tests revealed that these hybrids were the most active analgesic/anti-inflammatory agents, with improved ulcerogenic and cardioprotective properties. Finally, the most active dual inhibitors were docked into COX-2/sEH active regions to explain their binding mechanisms.
一些环氧化酶（COX）-2 选择性药物在上市几年后因心血管副作用而被撤出市场。在这项研究中，我们合成了一系列新型嘧啶/噻唑杂合体 7a-p，作为具有镇痛和抗炎作用且心脏毒性较低的选择性 COX-2/可溶性环氧化物水解酶（sEH）抑制剂。目标化合物被合成并在体外针对 COX-1、COX-2 和 sEH 酶进行了测试。杂合体 7j、7k 和 7i 表现出最强的 COX-2 抑制活性，被发现是最有效的双重 COX-2/sEH 抑制剂。体内试验表明，这些杂合体是最有效的镇痛/抗炎药物，具有改善的致溃疡和心脏保护特性。最后，最活跃的双重抑制剂被对接入 COX-2/sEH 的活性区域，以解释它们的结合机制。
