发现2-(3,5-二氟-4-甲磺酰胺基苯基)丙酰胺作为有效的瞬时受体电位香草酸亚型1（TRPV1）拮抗剂。
Discovery of 2-(3,5-difluoro-4-methylsulfonaminophenyl)propanamides as potent TRPV1 antagonists.
作者信息
Kim Changhoon, Ann Jihyae, Lee Sunho, Sun Wei, Blumberg Peter M, Frank-Foltyn Robert, Bahrenberg Gregor, Stockhausen Hannelore, Christoph Thomas, Lee Jeewoo
机构信息
Laboratory of Medicinal Chemistry, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea.
Shenyang Pharmaceutical University, Shenyang 110016, China.
出版信息
Bioorg Med Chem Lett. 2018 Aug 1;28(14):2539-2542. doi: 10.1016/j.bmcl.2018.05.043. Epub 2018 May 23.
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.
研究了一系列2-(3-氟-4-甲基磺酰胺基苯基)丙酰胺1的A区域类似物作为瞬时受体电位香草酸亚型1（TRPV1）拮抗剂。构效关系分析表明，3-（或/和）5位的氟基团以及4位的甲基磺酰胺基团对于拮抗辣椒素激活TRPV1最为理想。最有效的拮抗剂6不仅对辣椒素、低pH值和高温激活人TRPV1表现出强效拮抗作用，而且对辣椒素激活大鼠TRPV1也表现出高效拮抗作用。进一步研究表明，拮抗剂6在体内阻断了辣椒素的降温作用，与其体外作用机制一致，并且在福尔马林动物模型中显示出有前景的镇痛活性。
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