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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.
Bioorganic & Medicinal Chemistry Letters ( IF 2.5 ) Pub Date : 2020-09-12 , DOI: 10.1016/j.bmcl.2020.127548
Jin Mi Kang 1 , Sun Ok Kwon 1 , Jihyae Ann 1 , Peter M Blumberg 1 , Heejin Ha 2 , Young Dong Yoo 2 , Robert Frank-Foltyn 3 , Bernhard Lesch 3 , Gregor Bahrenberg 3 , Hannelore Stockhausen 3 , Thomas Christoph 3 , Jeewoo Lee 1
Affiliation  

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.



中文翻译:

发现1-(1H-吲唑-4-基)-3-((1-苯基-1H-吡唑-5-基)甲基)尿素作为有效和热中性TRPV1拮抗剂。

研究了一系列1-吲唑-3-(1-苯基吡唑-5-基)甲基脲作为h TRPV1拮抗剂。系统地研究了吲唑A区和3-三氟甲基/叔丁基吡唑C区的结构-活性关系,以优化对辣椒素活化的拮抗作用。其中,拮抗剂265051显示具有高度有效的拮抗作用ķ(CAP) = 0.4-0.5纳米。此外,小鼠体内的研究表明,这些衍生物均拮抗辣椒素诱导的体温过低,与它们的体外相符活动,并且他们自己没有诱发热疗。在福尔马林模型中,51以剂量依赖性方式显示出抗伤害感受活性。

更新日期:2020-09-12
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