2-(3-Fluoro-4-methylsulfonylaminophenyl)propanamides as potent TRPV1 antagonists: Structure activity relationships of the 2-oxy pyridine C-region

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• 作者：Shivaji A. Thorat^a ; Dong Wook Kang^a ; ^e ; HyungChul Ryu^a ; Myeong Seop Kim^a ; Ho Shin Kim^a ; Jihyae Ann^a ; Taehwan Ha^a ; Sung-Eun Kim^a ; Karam Son^b ; Sun Choi^b ; Peter M. Blumberg^c ; Robert Frank^d ; Gregor Bahrenberg^d ; Klaus Schiene^d ; Thomas Christoph^d ; Jeewoo Lee^a ; ^{jeewoo@snu.ac.kr}
• 关键词：TRPV1 antagonists ; Analgesic ; Molecular modeling ; Capsaicin
• 刊名：European Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：June, 2013
• 年：2013
• 卷：64
• 期：Complete
• 页码：589-602
• 全文大小：2173 K

文摘

The structure activity relationships of 2-oxy pyridine derivatives in the C-region of N-(6-trifluoromethyl-pyridin-3-ylmethyl) 2-(3-fluoro-4-methylsulfonylaminophenyl)propanamides as hTRPV1 antagonists were investigated. The analysis indicated that the lipophilicity of the 2-oxy substituents was critical for potent antagonism and 4 or 5 carbons appeared to be optimal for activity. Multiple compounds proved to have comparable activity to 1, which had been reported as the most potent antagonist for capsaicin activity among the previous series of compounds. Further analysis of compounds 22 (2-isobutyloxy) and 53 (2-benzyloxy) in the formalin test in mice demonstrated strong analgesic activity with full efficacy. Docking analysis of 53S using our hTRPV1 homology model indicated that the A- and B-region 2-(3-fluoro-4-methylsulfonylaminophenyl)propanamide made important hydrophobic and hydrogen bonding interactions with Tyr511 and that the C-region 6-trifluoromethyl and 2-benzyloxy groups of pyridine occupied the two hydrophobic binding pockets, respectively.