Solid-phase combinatorial approach for the optimization of soluble epoxide hydrolase inhibitors

被引：27

作者：

Hwang, Sung Hee

Morisseau, Christophe

Do, Zung

Hammock, Bruce D.

机构：

[1] Univ Calif Davis, Dept Entomol, Davis, CA 95616 USA

[2] Univ Calif Davis, Ctr Canc, Davis, CA 95616 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2006年 / 16卷 / 22期

关键词：

soluble epoxide hydrolase; urea; hypertension; anti-inflammation;

D O I：

10.1016/j.bmcl.2006.08.078

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A 192-member library of N,N'-disubstituted urea inhibitors was synthesized by a solid-phase method. The ureas were tested for their inhibitory activities against recombinant human soluble epoxide hydrolase. Simple carbocyclic or paralmeta-substituted phenyl groups showed inhibition potencies that were equal to or greater than adamantane-based sEH inhibitors, while the presence of bulky or ionizable groups close to the urea group dramatically decreased their activities. (c) 2006 Elsevier Ltd. All rights reserved.

引用

收藏

页码：5773 / 5777

页数：5

相关论文

共 24 条

[1] Expedient synthesis of secondary amines bound to indole resin and cleavage of resin-bound urea, amide and sulfonamide under mild conditions [J].

Bhattacharyya, S ;

Gooding, OW ;

Labadie, J .

TETRAHEDRON LETTERS, 2003, 44 (32) :6099-6102

[2]

Capdevila JH, 2000, J LIPID RES, V41, P163

[3] 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

[4] Cytochrome P4502C is an EDHF synthase in coronary arteries [J].

Fisslthaler, B ;

Popp, R ;

Kiss, L ;

Potente, M ;

Harder, DR ;

Fleming, I ;

Busse, R .

NATURE, 1999, 401 (6752) :493-497

[5] Epoxide hydrolases: biochemistry and molecular biology [J].

Fretland, AJ ;

Omiecinski, CJ .

CHEMICO-BIOLOGICAL INTERACTIONS, 2000, 129 (1-2) :41-59

[6] 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

[7] Soluble epoxide hydrolase inhibition lowers arterial blood pressure in angiotensin II hypertension [J].

Imig, JD ;

Zhao, XY ;

Capdevila, JH ;

Morisseau, C ;

Hammock, BD .

HYPERTENSION, 2002, 39 (02) :690-694

[8] Synthesis and SAR of conformationally restricted inhibitors of soluble epoxide hydrolase [J].

Jones, Paul D. ;

Tsai, Hsing-Ju ;

Do, Zung N. ;

Morisseau, Christophe ;

Hammock, Bruce D. .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2006, 16 (19) :5212-5216

[9] 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

[10] Optimization of amide-based inhibitors of soluble epoxide hydrolase with improved water solubility [J].

Kim, IH ;

Heirtzler, FR ;

Morisseau, C ;

Nishi, K ;

Tsai, HJ ;

Hammock, BD .

JOURNAL OF MEDICINAL CHEMISTRY, 2005, 48 (10) :3621-3629