Discovery of 1-(1H-indazol-4-yl)-3-((1-phenyl-1H-pyrazol-5-yl)methyl) ureas as potent and thermoneutral TRPV1 antagonists

被引：8

作者：

Kang, Jin Mi ^{[1
]}

Kwon, Sun Ok ^{[1
]}

Ann, Jihyae ^{[1
]}

Blumberg, Peter M. ^{[1
]}

Ha, Heejin ^{[2
]}

Yoo, Young Dong ^{[2
]}

Frank-Foltyn, Robert ^{[3
]}

Lesch, Bernhard ^{[3
]}

Bahrenberg, Gregor ^{[3
]}

Stockhausen, Hannelore ^{[3
]}

Christoph, Thomas ^{[3
]}

Lee, Jeewoo ^{[1
]}

机构：

[1] Seoul Natl Univ, Coll Pharm, Lab Med Chem, Seoul 08826, South Korea

[2] Medifron DBT, Seoul 08502, South Korea

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

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2020年 / 30卷 / 23期

基金：

新加坡国家研究基金会;

关键词：

Vanilloid Receptor 1; TRPV1; Antagonist; Analgesic; VANILLOID-1; ANTAGONISTS; CAPSAICIN RECEPTOR; PAIN; ABT-102; 2-(3-FLUORO-4-METHYLSULFONYLAMINOPHENYL)PROPANAMIDES; PHARMACOLOGY; ACTIVATION; ANALOGS;

D O I：

10.1016/j.bmcl.2020.127548

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A series of 1-indazol-3-(1-phenylpyrazol-5-yl)methyl ureas were investigated as hTRPV1 antagonists. The structure-activity relationship study was conducted systematically for both the indazole A-region and the 3-trifluoromethyl/t-butyl pyrazole C-region to optimize the antagonism toward the activation by capsaicin. Among them, the antagonists 26, 50 and 51 displayed highly potent antagonism with Ki(CAP) = 0.4-0.5 nM. Further, in vivo studies in mice indicated that these derivatives both antagonized capsaicin induced hypothermia, consistent with their in vitro activity, and themselves did not induce hyperthermia. In the formalin model, 51 showed antinociceptive activity in a dose-dependent manner.

引用

页数：6

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