Structure-based optimization of the piperazino-containing 1,3-disubstituted ureas affording sub-nanomolar inhibitors of soluble epoxide hydrolase

被引：15

作者：

Huang, Shao-Xu ^{[1
]}

Cao, Bin ^{[1
]}

Morisseau, Christophe ^{[2
,3
]}

Tin, Yi ^{[4
]}

Hammock, Bruce D. ^{[2
,3
]}

Long, Ya-Qiu ^{[1
]}

机构：

[1] Chinese Acad Sci, Shanghai Inst Biol 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

[4] Yunnan Univ, Sch Chem Sci & Technol, Kunming 650091, Peoples R China

来源：

MEDCHEMCOMM | 2012年 / 3卷 / 03期

基金：

中国国家自然科学基金;

关键词：

EPOXYEICOSATRIENOIC ACIDS; TRPV4; METABOLISM; PROTECTS; CHANNELS; TARGET; ROLES;

D O I：

10.1039/c2md00288d

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

The inhibition of the soluble epoxide hydrolase (sEH) is a promising new therapy in the treatment of cardiovascular, inflammation and other disorders. A piperazino functionality as the tertiary pharmacophore remarkably improved the drug-like profile of the 1,3-disubstituted urea sEH inhibitors. However, the potency was more dependent on the overall best balance of the hydrophilicity and lipophilicity. Based on the sEH-inhibitor complex structure, further structural optimization on the piperazino-containing 1,3-disubstituted urea scaffold was conducted for an improved potency. The 1-adamantylacetamide and para-phenylcarbonyl group were identified to be an optimal primary pharmacophore and secondary pharmacophore motif, respectively, generating sub-nanomolar sEH inhibitors with favorable water solubility.

引用

页码：379 / 384

页数：6

共 22 条

[1] 1-(1-Acetyl-piperidin-4-yl)-3-adamantan-1-yl-urea (AR9281) as a potent, selective, and orally available soluble epoxide hydrolase inhibitor with efficacy in rodent models of hypertension and dysglycemia [J].

Anandan, Sampath-Kumar ;

Webb, Heather Kay ;

Chen, Dawn ;

Wang, Yi-Xin ;

Aavula, Basker R. ;

Cases, Sylvaine ;

Cheng, Ying ;

Do, Zung N. ;

Mehra, Upasana ;

Vinh Tran ;

Vincelette, Jon ;

Waszczuk, Joanna ;

White, Kathy ;

Wong, Kenneth R. ;

Zhang, Le-Ning ;

Jones, Paul D. ;

Hammock, Bruce D. ;

Patel, Dinesh V. ;

Whitcomb, Randall ;

MacIntyre, D. Euan ;

Sabry, James ;

Gless, Richard .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2011, 21 (03) :983-988

[2] TRPV4 forms a novel Ca2+ signaling complex with ryanodine receptors and BKCa channels [J].

Earley, S ;

Heppner, TJ ;

Nelson, MT ;

Brayden, JE .

CIRCULATION RESEARCH, 2005, 97 (12) :1270-1279

[3] Human soluble epoxide hydrolase: Structural basis of inhibition by 4-(3-cyclohexylureido)-carboxylic acids [J].

Gomez, GA ;

Morisseau, C ;

Hammock, BD ;

Christianson, DW .

PROTEIN SCIENCE, 2006, 15 (01) :58-64

[4] 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].

Huang, Shao-Xu ;

Li, Hui-Yuan ;

Liu, Jun-Yan ;

Morisseau, Christophe ;

Hammock, Bruce D. ;

Long, Ya-Qiu .

JOURNAL OF MEDICINAL CHEMISTRY, 2010, 53 (23) :8376-8386

[5] Soluble epoxide hydrolase as a therapeutic target for cardiovascular diseases [J].

Imig, John D. ;

Hammock, Bruce D. .

NATURE REVIEWS DRUG DISCOVERY, 2009, 8 (10) :794-805

[6] Fluorescent substrates for soluble epoxide hydrolase and application to inhibition studies [J].

Jones, PD ;

Wolf, NM ;

Morisseau, C ;

Whetstone, P ;

Hock, B ;

Hammock, BD .

ANALYTICAL BIOCHEMISTRY, 2005, 343 (01) :66-75

[7] Beyond vasodilatation: non-vasomotor roles of epoxyeicosatrienoic acids in the cardiovascular system [J].

Larsen, Brandon T. ;

Campbell, William B. ;

Gutterman, David D. .

TRENDS IN PHARMACOLOGICAL SCIENCES, 2007, 28 (01) :32-38

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

Li, Hui-Yuan ;

Jin, Yi ;

Morisseau, Christophe ;

Hammock, Bruce D. ;

Long, Ya-Qiu .

BIOORGANIC & MEDICINAL CHEMISTRY, 2006, 14 (19) :6586-6592

[9] Soluble Epoxide Hydrolase, a Target with Multiple Opportunities for Cardiovascular Drug Discovery [J].

Marino, Joseph P., Jr. .

CURRENT TOPICS IN MEDICINAL CHEMISTRY, 2009, 9 (05) :452-463

[10] Epoxide hydrolases: Mechanisms, inhibitor designs, and biological roles [J].

Morisseau, C ;

Hammock, BD .

ANNUAL REVIEW OF PHARMACOLOGY AND TOXICOLOGY, 2005, 45 :311-+

← 1 2 3 →