Pyrazole C-region analogues of 2-(3-fluoro-4-methylsulfonylaminophenyl)propanamides as potent TRPV1 antagonists

被引：22

作者：

Lee, Sunho ^{[1
]}

Kim, Changhoon ^{[1
]}

Ann, Jihyae ^{[1
]}

Thorat, Shivaji A. ^{[1
]}

Kim, Eunhye ^{[2
]}

Park, Jongmi ^{[2
]}

Choi, Sun ^{[2
]}

Blumberg, Peter M. ^{[3
]}

Frank-Foltyn, Robert ^{[4
]}

Bahrenberg, Gregor ^{[4
]}

Stockhausen, Hannelore ^{[4
]}

Christoph, Thomas ^{[4
]}

Lee, Jeewoo ^{[1
]}

机构：

[1] Seoul Natl Univ, Pharmaceut Sci Res Inst, Coll Pharm, Med Chem Lab, Seoul 08826, South Korea

[2] Ewha Womans Univ, Grad Sch Pharmaceut Sci, Coll Pharm, Natl Leading Res Lab Mol Modeling & Drug Design, Seoul 03760, South Korea

[3] NCI, Lab Canc Biol & Genet, Ctr Canc Res, NIH, Bethesda, MD 20892 USA

[4] Grunenthal GmbH, Grunenthal Innovat, D-52078 Aachen, Germany

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2017年 / 27卷 / 18期

基金：

新加坡国家研究基金会; 美国国家卫生研究院;

关键词：

Vanilloid receptor 1; TRPV1; antagonist; Molecular modeling; CAPSAICIN RECEPTOR; ION-CHANNEL; PYRIDINE; 2-(3-FLUORO-4-METHYLSULFONAMIDOPHENYL)PROPANAMIDES; PHARMACOLOGY; ACTIVATION; NOCISENSOR; DOCKING;

D O I：

10.1016/j.bmcl.2017.08.020

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A series of 1-substituted 3-(t-butyl/trifluoromethyl)pyrazole C-region analogues of 2-(3-fluoro-4-methyl-sulfonamidophenyl) propanamides were investigated for hTRPV1 antagonism. The structure activity relationship indicated that the 3-chlorophenyl group at the 1-position of pyrazole was the optimized hydrophobic group for antagonistic potency and the activity was stereospecific to the S-configuration, providing exceptionally potent antagonists 13S and 16S with K-i(CAP) = 0.1 nM. Particularly significant, 13S exhibited antagonism selective for capsaicin and NADA and not for low pH or elevated temperature. Both compounds also proved to be very potent antagonists for rTRPV1, blocking in vivo the hypothermic action of capsaicin, consistent with their in vitro mechanism. The docking study of compounds 13S and 16S in our hTRPV1 homology model indicated that the binding modes differed somewhat, with that of 13S more closely resembling that of GRT12360. (C) 2017 Elsevier Ltd. All rights reserved.

引用

页码：4383 / 4388

页数：6

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