alpha-Substituted 2-(3-fluoro-4-methylsulfonamidophenyl)acetamides as potent TRPV1 antagonists

作者：Phuong Thao Tran; Kim Ho Shin; Ann Jihyae; Kim Sung Eun; Kim Changhoon; Hong Mannkyu; Hoang Van Hai; Ngo Van T H; Hong Sunhye; Cui Minghua; Choi Sun; Blumberg Peter M; Frank Foltyn Robert; Bahrenberg Gregor; Stockhausen Hannelore; Christoph Thomas; Lee Jeewoo^*

来源：Bioorganic & Medicinal Chemistry Letters, 2015, 25(11): 2326-2330.

DOI：10.1016/j.bmcl.2015.04.024

• TRPV1 antagonist
• Analgesic
• Capsaicin
• Molecular modeling

A series of alpha-substituted acetamide derivatives of previously reported 2-(3-fluoro-4-methylsulfonamidophenyl) propanamide leads (1, 2) were investigated for antagonism of hTRPV1 activation by capsaicin. Compound 34, which possesses an alpha-m-tolyl substituent, showed highly potent and selective antagonism of capsaicin with K-i(CAP) = 0.1 nM. It thus reflected a 3-fold improvement in potency over parent 1. Docking analysis using our homology model indicated that the high potency of 34 might be attributed to a specific hydrophobic interaction of the m-tolyl group with the receptor.

• 出版日期2015-6-1