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

Abstract：

: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 anti-nociceptive activity in a dose-dependent manner.

journal_name

Bioorg Med Chem Lett

journal_title

Bioorganic & medicinal chemistry letters

authors

Kang JM,Kwon SO,Ann J,Blumberg PM,Ha H,Yoo YD,Frank-Foltyn R,Lesch B,Bahrenberg G,Stockhausen H,Christoph T,Lee J

doi

10.1016/j.bmcl.2020.127548

subject

Has Abstract

pub_date

2020-12-01 00:00:00

pages

127548

issue

23

eissn

0960-894X

issn

1464-3405

pii

S0960-894X(20)30659-4

journal_volume

30

pub_type

杂志文章

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