The 5-substituted piperazine as a novel secondary pharmacophore greatly improving the physical properties of urea-based inhibitors of soluble epoxide hydrolase
文献类型：期刊论文
| 作者 | Li, Hui-Yuan; Jin, Yi ; Morisseau, Christophe; Hammock, Bruce D.; Long, Ya-Qiu
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| 刊名 | BIOORGANIC & MEDICINAL CHEMISTRY
 |
| 出版日期 | 2006-10-01 |
| 卷号 | 14期号:19页码:6586-6592 |
| 关键词 | soluble epoxide hydrolase 1-adamantanyl-urea-based inhibitors piperazine chiral pool synthesis secondary pharmacophore water solubility hypertension vascular inflammation |
| ISSN号 | 0968-0896 |
| DOI | 10.1016/j.bmc.2006.06.005 |
| 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 hypertention and inflammation. The problems of limited water solubility and high melting points commonly displayed by the active 1,3-disubstituted ureas prevent the further development of potent urea-based sEH inhibitors. Therefore, a new class of potent inhibitors of sEH were designed and synthesized by the introduction of a polar constrained piperazino group in the right side of adasmantyl urea to increase the water solubility. A facile and general synthesis was established to prepare a series of 1-adamantan-1-yl-3-(2-piperazin-2-yl-ethyl)-ureas (1a-d) with various 5-substitutions on the 2-piperazino ring, which will advance the SAR study by the efficient making of structurally diverse analogs. The effect of the 5-substitution on the activity and the water solubility was examined. The best potency was exhibited by the 5-benzyl-substituted-piperazine-containing urea with an IC50 value of 1.37 mu M against human sEH and good water solubility (S = 7.46 mg/mL) and low melting point, in which the 5-substituted piperazine serves as a favorable secondary pharmacophore and a water-solubility enhancing group. Our present work provides a promising new template for the design of orally available therapeutic agents for the disorders that can be addressed by changing the in vivo concentration of the chemical mediators that contain an epoxide. (c) 2006 Elsevier Ltd. All rights reserved. |
| WOS关键词 | WATER SOLUBILITY ; EPOXYEICOSATRIENOIC ACIDS ; BIOACTIVATION ; ROLES |
| 资助项目 | NIEHS NIH HHS[R37 ES02710] ; NIEHS NIH HHS[R37 ES002710] |
| WOS研究方向 | Biochemistry & Molecular Biology ; Pharmacology & Pharmacy ; Chemistry |
| 语种 | 英语 |
| WOS记录号 | WOS:000240650500013 |
| 出版者 | PERGAMON-ELSEVIER SCIENCE LTD |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/273478]  |
| 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.Univ Calif Davis, Dept Entomol, Davis, CA 95616 USA 2.Chinese Acad Sci, Shanghai Inst Biol Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China 3.Univ Calif Davis, Ctr Canc, Davis, CA 95616 USA |
| 推荐引用方式 GB/T 7714 | Li, Hui-Yuan,Jin, Yi,Morisseau, Christophe,et al. The 5-substituted piperazine as a novel secondary pharmacophore greatly improving the physical properties of urea-based inhibitors of soluble epoxide hydrolase[J]. BIOORGANIC & MEDICINAL CHEMISTRY,2006,14(19):6586-6592. |
| APA | Li, Hui-Yuan,Jin, Yi,Morisseau, Christophe,Hammock, Bruce D.,&Long, Ya-Qiu.(2006).The 5-substituted piperazine as a novel secondary pharmacophore greatly improving the physical properties of urea-based inhibitors of soluble epoxide hydrolase.BIOORGANIC & MEDICINAL CHEMISTRY,14(19),6586-6592. |
| MLA | Li, Hui-Yuan,et al."The 5-substituted piperazine as a novel secondary pharmacophore greatly improving the physical properties of urea-based inhibitors of soluble epoxide hydrolase".BIOORGANIC & MEDICINAL CHEMISTRY 14.19(2006):6586-6592. |
入库方式： OAI收割
来源：上海药物研究所
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