Gur Maz Tugce, Koc Beyzanur, Jordan Paul M, İbiş Kübra, Çalışkan Burcu, Werz Oliver, Banoglu Erden
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, Taç Sok. No:3 Yenimahalle, 06560 Ankara, Turkey.
Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich Schiller University Jena, Philosophenweg 14, D-7743 Jena, Germany.
ACS Omega. 2023 Jan 4;8(2):2445-2454. doi: 10.1021/acsomega.2c06936. eCollection 2023 Jan 17.
Inhibition of soluble epoxide hydrolase (sEH) is indicated as a new therapeutic modality against a variety of inflammatory diseases, including metabolic, renal, and cardiovascular disorders. In our ongoing research on sEH inhibitors, we synthesized novel benzoxazolone-5-urea analogues with highly potent sEH inhibitory properties inspired by the crystallographic fragment scaffolds incorporating a single H-bond donor/acceptor pair. The tractable SAR results indicated that the aryl or benzyl fragments flanking the benzoxazolone-urea scaffold conferred potent sEH inhibition, and compounds inhibited the sEH activity with IC values in the range of 0.39-570 nM. Docking studies and molecular dynamics simulations with the most potent analogue provided valuable insights into potential binding interactions of the inhibitor in the sEH binding region. In conclusion, benzoxazolone-5-ureas furnished with benzyl groups on the urea function can be regarded as novel lead structures, which allow the development of advanced analogues with enhanced properties against sEH.
抑制可溶性环氧化物水解酶（sEH）被认为是一种针对多种炎症性疾病的新治疗方式，这些疾病包括代谢、肾脏和心血管疾病。在我们正在进行的关于sEH抑制剂的研究中，受包含单个氢键供体/受体对的晶体学片段支架启发，我们合成了具有高效sEH抑制特性的新型苯并恶唑酮-5-脲类似物。易于处理的构效关系（SAR）结果表明，苯并恶唑酮-脲支架两侧的芳基或苄基片段赋予了强大的sEH抑制作用，化合物抑制sEH活性的IC值范围为0.39-570 nM。对最有效的类似物进行对接研究和分子动力学模拟，为抑制剂在sEH结合区域的潜在结合相互作用提供了有价值的见解。总之，在脲官能团上带有苄基的苯并恶唑酮-5-脲可被视为新型先导结构，这有助于开发具有更强抗sEH性能的先进类似物。
