Structure activity relationships of benzyl C-region analogs of 2-(3-fluoro-4-methylsulfonamidophenyl)propanamides as potent TRPV1 antagonists

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• 作者：Jihyae Ann^a ; Aeran Jung^a ; Mi-Yeon Kim^a ; Hyuk-Min Kim^a ; HyungChul Ryu^b ; Sunjoo Kim^b ; Dong Wook Kang^c ; Sunhye Hong^d ; Minghua Cui^d ; Sun Choi^d ; Peter M. Blumberg^e ; Robert Frank-Foltyn^f ; Gregor Bahrenberg^f ; Hannelore Stockhausen^f ; Thomas Christoph^f ; Jeewoo Lee^a ; ^{jeewoo@snu.ac.kr" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Vanilloid receptor 1 ; TRPV1 antagonists ; Analgesic
• 刊名：Bioorganic & Medicinal Chemistry
• 出版年：2015
• 出版时间：1 November 2015
• 年：2015
• 卷：23
• 期：21
• 页码：6844-6854
• 全文大小：6069 K

文摘

A series of 2-substituted 4-(trifluoromethyl)benzyl C-region analogs of 2-(3-fluoro-4-methylsulfonamidophenyl)propanamides were investigated for hTRPV1 antagonism. The analysis indicated that the phenyl C-region derivatives exhibited better antagonism than those of the corresponding pyridine surrogates for most of the series examined. Among the phenyl C-region derivatives, the two best compounds 43 and 44S antagonized capsaicin selectively relative to their antagonism of other activators and showed excellent potencies with K_i(CAP) = 0.3 nM. These two compounds blocked capsaicin-induced hypothermia, consistent with TRPV1 as their site of action, and they demonstrated promising analgesic activities in a neuropathic pain model without hyperthermia. The docking study of 44S in our hTRPV1 homology model indicated that its binding mode was similar with that of its pyridine surrogate in the A- and B-regions but displayed a flipped configuration in the C-region.