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

Autor: Kang JM; Laboratory of Medicinal Chemistry, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea., Kwon SO; Laboratory of Medicinal Chemistry, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea., Ann J; Laboratory of Medicinal Chemistry, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea., Blumberg PM; Laboratory of Medicinal Chemistry, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea., Ha H; Medifron DBT, Seoul 08502, Republic of Korea., Yoo YD; Medifron DBT, Seoul 08502, Republic of Korea., Frank-Foltyn R; Grünenthal Innovation, Grünenthal GmbH, D-52078 Aachen, Germany., Lesch B; Grünenthal Innovation, Grünenthal GmbH, D-52078 Aachen, Germany., Bahrenberg G; Grünenthal Innovation, Grünenthal GmbH, D-52078 Aachen, Germany., Stockhausen H; Grünenthal Innovation, Grünenthal GmbH, D-52078 Aachen, Germany., Christoph T; Grünenthal Innovation, Grünenthal GmbH, D-52078 Aachen, Germany., Lee J; Laboratory of Medicinal Chemistry, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea. Electronic address: jeewoo@snu.ac.kr.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2020 Dec 01; Vol. 30 (23), pp. 127548. Date of Electronic Publication: 2020 Sep 12.
DOI: 10.1016/j.bmcl.2020.127548
Abstrakt: 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 K i (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.
(Copyright © 2020 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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