Discovery of 2-(3,5-difluoro-4-methylsulfonaminophenyl)propanamides as potent TRPV1 antagonists |
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| Authors: | Changhoon Kim Jihyae Ann Sunho Lee Wei Sun Peter M. Blumberg Robert Frank-Foltyn Gregor Bahrenberg Hannelore Stockhausen Thomas Christoph Jeewoo Lee |
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| Affiliation: | 1. Laboratory of Medicinal Chemistry, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea;2. Shenyang Pharmaceutical University, Shenyang 110016, China;3. Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892-4255, USA;4. Grünenthal Innovation, Grünenthal GmbH, D-52078 Aachen, Germany |
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| Abstract: | A series of A-region analogues of 2-(3-fluoro-4-methylsufonamidophenyl) propanamide 1 were investigated as TRPV1 antagonists. The analysis of structure-activity relationship indicated that a fluoro group at the 3- (or/and) 5-position and a methylsulfonamido group at the 4-position were optimal for antagonism of TRPV1 activation by capsaicin. The most potent antagonist 6 not only exhibited potent antagonism of activation of hTRPV1 by capsaicin, low pH and elevated temperature but also displayed highly potent antagonism of activation of rTRPV1 by capsaicin. Further studies demonstrated that antagonist 6 blocked the hypothermic effect of capsaicin in vivo, consistent with its in vitro mechanism, and it showed promising analgesic activity in the formalin animal model. |
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| Keywords: | Vanilloid receptor 1 TRPV1 antagonist Analgesic |
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