Incorporation of Piperazino Functionality into 1,3-Disubstituted Urea as the Tertiary Pharmacophore Affording Potent Inhibitors of Soluble Epoxide Hydrolase with Improved Pharmacokinetic Properties
文献类型：期刊论文
| 作者 | Huang, Shao-Xu1; Li, Hui-Yuan1; Liu, Jun-Yan2; Morisseau, Christophe2,3; Hammock, Bruce D.2,3; Long, Ya-Qiu1 |
| 刊名 | JOURNAL OF MEDICINAL CHEMISTRY
 |
| 出版日期 | 2010-12-09 |
| 卷号 | 53期号:23页码:8376-8386 |
| ISSN号 | 0022-2623 |
| DOI | 10.1021/jm101087u |
| 文献子类 | Article |
| 英文摘要 | 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: T-1/2 = 14 h, C-max, = 84 nM, AUC = 40 200 nM . min, and IC50 = 7.0 nM against human sEH enzyme. |
| WOS关键词 | EPOXYEICOSATRIENOIC ACIDS ; WATER SOLUBILITY ; BLOOD-PRESSURE ; CYTOCHROME-P450 ; HYPERTENSION ; DISCOVERY ; DESIGN ; LIVER ; OPTIMIZATION ; PURIFICATION |
| 资助项目 | National Science and Technology Major Project "Key New Drug Creation and Manufacturing Program", China[2009ZX09301-001] ; National Science and Technology Major Project "Key New Drug Creation and Manufacturing Program", China[2009ZX09103-067] ; NIEHS[R01 ES002710] ; NIH/NHLBI[Ro1 HL059699] |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:000284738400017 |
| 出版者 | AMER CHEMICAL SOC |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/278691]  |
| 专题 | 药物化学研究室 中科院受体结构与功能重点实验室 新药研究国家重点实验室 |
| 通讯作者 | Long, Ya-Qiu |
| 作者单位 | 1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China; 2.Univ Calif Davis, Dept Entomol, Davis, CA 95616 USA; 3.Univ Calif Davis, Ctr Canc, Davis, CA 95616 USA |
| 推荐引用方式 GB/T 7714 | Huang, Shao-Xu,Li, Hui-Yuan,Liu, Jun-Yan,et al. Incorporation of Piperazino Functionality into 1,3-Disubstituted Urea as the Tertiary Pharmacophore Affording Potent Inhibitors of Soluble Epoxide Hydrolase with Improved Pharmacokinetic Properties[J]. JOURNAL OF MEDICINAL CHEMISTRY,2010,53(23):8376-8386. |
| APA | Huang, Shao-Xu,Li, Hui-Yuan,Liu, Jun-Yan,Morisseau, Christophe,Hammock, Bruce D.,&Long, Ya-Qiu.(2010).Incorporation of Piperazino Functionality into 1,3-Disubstituted Urea as the Tertiary Pharmacophore Affording Potent Inhibitors of Soluble Epoxide Hydrolase with Improved Pharmacokinetic Properties.JOURNAL OF MEDICINAL CHEMISTRY,53(23),8376-8386. |
| MLA | Huang, Shao-Xu,et al."Incorporation of Piperazino Functionality into 1,3-Disubstituted Urea as the Tertiary Pharmacophore Affording Potent Inhibitors of Soluble Epoxide Hydrolase with Improved Pharmacokinetic Properties".JOURNAL OF MEDICINAL CHEMISTRY 53.23(2010):8376-8386. |
入库方式： OAI收割
来源：上海药物研究所
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