Incorporation of Piperazino Functionality into 1,3-Disubstituted Urea as the Tertiary Pharmacophore Affording Potent Inhibitors of Soluble Epoxide Hydrolase with Improved Pharmacokinetic Properties

详细信息    查看全文

• 作者：Shao-Xu Huang ; Hui-Yuan Li ; Jun-Yan Liu ; Christophe Morisseau ; Bruce D. Hammock ; Ya-Qiu Long
• 刊名：Journal of Medicinal Chemistry
• 出版年：2010
• 出版时间：December 9, 2010
• 年：2010
• 卷：53
• 期：23
• 页码：8376-8386
• 全文大小：1048K
• 年卷期：v.53,no.23(December 9, 2010)
• ISSN：1520-4804

文摘

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 N⁴-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: T_1/2 =14 h, C_max = 84 nM, AUC = 40200 nM·min, and IC₅₀ = 7.0 nM against human sEH enzyme.