The 5-substituted piperazine as a novel secondary pharmacophore greatly improving the physical properties of urea-based inhibitors of soluble epoxide hydrolase

doi:10.1016/j.bmc.2006.06.005

	The 5-substituted piperazine as a novel secondary pharmacophore greatly improving the physical properties of urea-based inhibitors of soluble epoxide hydrolase
	Li, Hui-Yuan ; Jin, Yi; Morisseau, Christophe ; Hammock, Bruce D.; Long, Ya-Qiu
刊名	BIOORGANIC & MEDICINAL CHEMISTRY
	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.
资助项目	NIEHS NIH HHS[R37 ES02710] ; NIEHS NIH HHS[R37 ES002710]
WOS关键词	WATER SOLUBILITY ; EPOXYEICOSATRIENOIC ACIDS ; BIOACTIVATION ; ROLES
WOS研究方向	Biochemistry & Molecular Biology ; Pharmacology & Pharmacy ; Chemistry
语种	英语
出版者	PERGAMON-ELSEVIER SCIENCE LTD
WOS记录号	WOS:000240650500013
内容类型	期刊论文
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.