State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
J Med Chem. 2010 Dec 9;53(23):8376-86. doi: 10.1021/jm101087u. Epub 2010 Nov 11.
The inhibition of the mammalian soluble epoxide hydrolase (sEH) is a promising new therapy in the treatment of hypertension, inflammation, and other disorders. However, the problems of limited water solubility, high melting point, and low metabolic stability complicated the development of 1,3-disubstituted urea-based sEH inhibitors. The current study explored the introduction of the substituted piperazino group as the tertiary pharmacophore, which resulted in substantial improvements in pharmacokinetic parameters over previously reported 1-adamantylurea based inhibitors while retaining high potency. The SAR studies revealed that the meta- or para-substituted phenyl spacer and N(4)-acetyl or sulfonyl substituted piperazine were optimal structures for achieving high potency and good physical properties. The 1-(4-(4-(4-acetylpiperazin-1-yl)butoxy)phenyl)-3-adamantan-1-yl urea (29c) demonstrated excellent in vivo pharmacokinetic properties in mice: T1/2 =14 h, Cmax = 84 nM, AUC = 40 200 nM·min, and IC50 = 7.0 nM against human sEH enzyme.
哺乳动物可溶性环氧化物水解酶（sEH）的抑制作用是治疗高血压、炎症和其他疾病的一种有前途的新疗法。然而，水溶性有限、熔点高和代谢稳定性低等问题使基于 1,3-二取代脲的 sEH 抑制剂的开发变得复杂。本研究探索了引入取代哌嗪基作为三级药效基团，与以前报道的基于 1-金刚烷脲的抑制剂相比，在保留高活性的同时，显著改善了药代动力学参数。SAR 研究表明，间位或对位取代的苯基间隔基和 N(4)-乙酰基或磺酰基取代的哌嗪是获得高活性和良好物理性质的最佳结构。1-(4-(4-(4-乙酰基哌嗪-1-基)丁氧基)苯基)-3-金刚烷-1-基脲（29c）在小鼠体内表现出优异的药代动力学性质：T1/2 =14 h，Cmax = 84 nM，AUC = 40 200 nM·min，IC50 = 7.0 nM，对人 sEH 酶具有抑制作用。
