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α-取代的2-(3-氟-4-甲基磺酰胺基苯基)乙酰胺作为有效的瞬时受体电位香草酸亚型1（TRPV1）拮抗剂。

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

作者信息

Tran Phuong-Thao, 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

机构信息

Laboratory of Medicinal Chemistry, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea.

National Leading Research Laboratory of Molecular Modeling & Drug Design, College of Pharmacy, Graduate School of Pharmaceutical Sciences, and Global Top 5 Research Program, Ewha Womans University, Seoul 120-750, Republic of Korea.

出版信息

Bioorg Med Chem Lett. 2015 Jun 1;25(11):2326-30. doi: 10.1016/j.bmcl.2015.04.024. Epub 2015 Apr 12.

DOI:10.1016/j.bmcl.2015.04.024
PMID:25937016
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6957262/
Abstract

A series of α-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 α-m-tolyl substituent, showed highly potent and selective antagonism of capsaicin with Ki(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.

摘要

对先前报道的2-(3-氟-4-甲基磺酰胺基苯基)丙酰胺类先导化合物(1,2)的一系列α-取代乙酰胺衍生物进行了研究，以考察其对辣椒素激活人瞬时受体电位香草酸亚型1(hTRPV1)的拮抗作用。具有α-间甲苯基取代基的化合物34对辣椒素表现出高效且选择性的拮抗作用，其Ki(CAP)=0.1 nM。因此，其效力比母体化合物1提高了3倍。使用我们的同源模型进行的对接分析表明，化合物34的高效力可能归因于间甲苯基与受体之间特定的疏水相互作用。

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本文引用的文献

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2-Alkyl/alkenyl substituted pyridine C-region analogues of 2-(3-fluoro-4-methylsulfonylaminophenyl)propanamides as highly potent TRPV1 antagonists.2-(3-氟-4-甲基磺酰氨基苯基)丙酰胺的2-烷基/烯基取代吡啶C区类似物作为高效TRPV1拮抗剂。
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Discovery of N-(3-fluoro-4-methylsulfonamidomethylphenyl)urea as a potent TRPV1 antagonistic template.发现N-（3-氟-4-甲基磺酰胺基甲基苯基）脲作为一种有效的TRPV1拮抗剂模板。
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