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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。

2-Alkyl/alkenyl substituted pyridine C-region analogues of 2-(3-fluoro-4-methylsulfonylaminophenyl)propanamides as highly potent TRPV1 antagonists.

作者信息

Ryu HyungChul, Seo Sejin, Cho Seong-Hee, Kim Ho Shin, Jung Aeran, Kang Dong Wook, Son Karam, Cui Minghua, Hong Sun-hye, Sharma Pankaz Kumar, Choi Sun, Blumberg Peter M, Frank-Foltyn Robert, Bahrenberg Gregor, Stockhausen Hannelore, Schiene Klaus, Christoph Thomas, Frormann Sven, 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.

Laboratory of Medicinal Chemistry, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea; Department of Pharmaceutical Science and Technology, College of Health and Medical Science, Catholic University of Deagu, Gyeongsan-si, Gyeongsangbuk-do 712-702, Republic of Korea.

出版信息

Bioorg Med Chem Lett. 2014 Aug 15;24(16):4039-43. doi: 10.1016/j.bmcl.2014.05.074. Epub 2014 Jun 2.

DOI:10.1016/j.bmcl.2014.05.074
PMID:24948568
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6956567/
Abstract

A series of 2-alkyl/alkenyl pyridine C-region derivatives of 2-(3-fluoro-4-methylsulfonylaminophenyl)propanamides were investigated as hTRPV1 antagonists. Multiple compounds showed excellent and stereospecific TRPV1 antagonism with better potency than previous lead 2. Among them, compound 15f demonstrated a strong analgesic profile in a rat neuropathic pain model and blocked capsaicin-induced hypothermia in a dose-dependent manner. Docking analysis of (S)-15f with our hTRPV1 homology model provided insight into its specific binding mode.

摘要

研究了一系列2-(3-氟-4-甲基磺酰氨基苯基)丙酰胺的2-烷基/烯基吡啶C区域衍生物作为hTRPV1拮抗剂。多种化合物表现出优异的、立体特异性的TRPV1拮抗作用，效力优于先前的先导化合物2。其中，化合物15f在大鼠神经性疼痛模型中表现出强烈的镇痛作用，并以剂量依赖的方式阻断辣椒素诱导的体温过低。(S)-15f与我们的hTRPV1同源模型的对接分析揭示了其特定的结合模式。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/88ce/6956567/33aeb40ad15e/nihms-1065933-f0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/88ce/6956567/98fd182a7c77/nihms-1065933-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/88ce/6956567/19b37419c92f/nihms-1065933-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/88ce/6956567/ef5cdf2afb42/nihms-1065933-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/88ce/6956567/e0d28e5108c2/nihms-1065933-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/88ce/6956567/33aeb40ad15e/nihms-1065933-f0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/88ce/6956567/98fd182a7c77/nihms-1065933-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/88ce/6956567/19b37419c92f/nihms-1065933-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/88ce/6956567/ef5cdf2afb42/nihms-1065933-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/88ce/6956567/e0d28e5108c2/nihms-1065933-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/88ce/6956567/33aeb40ad15e/nihms-1065933-f0007.jpg

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本文引用的文献

1
TRPV1 antagonist with high analgesic efficacy: 2-Thio pyridine C-region analogues of 2-(3-fluoro-4-methylsulfonylaminophenyl)propanamides.具有高镇痛疗效的 TRPV1 拮抗剂：2-(3-氟-4-甲磺酰氨基苯基)丙酰胺的 2-噻吩基 C-区类似物。
Bioorg Med Chem. 2013 Nov 1;21(21):6657-64. doi: 10.1016/j.bmc.2013.08.015. Epub 2013 Aug 13.
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2-(3-Fluoro-4-methylsulfonylaminophenyl)propanamides as potent TRPV1 antagonists: structure activity relationships of the 2-oxy pyridine C-region.2-(3-氟-4-甲磺酰氨基苯基)丙酰胺类作为强效 TRPV1 拮抗剂：2-氧代吡啶 C 区的结构活性关系。
Eur J Med Chem. 2013 Jun;64:589-602. doi: 10.1016/j.ejmech.2013.04.003. Epub 2013 Apr 11.
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Screening TRPV1 antagonists for the treatment of pain: lessons learned over a decade.TRPV1 拮抗剂治疗疼痛的筛选：十余年的经验教训。
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Multisteric TRPV1 nocisensor: a target for analgesics.多聚体 TRPV1 伤害感受器：镇痛药的作用靶点。
Trends Pharmacol Sci. 2012 Dec;33(12):646-55. doi: 10.1016/j.tips.2012.09.002. Epub 2012 Oct 12.
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2-(3-fluoro-4-methylsulfonylaminophenyl)propanamides as potent transient receptor potential vanilloid 1 (TRPV1) antagonists: structure-activity relationships of 2-amino derivatives in the N-(6-trifluoromethylpyridin-3-ylmethyl) C-region.2-(3-氟-4-甲磺酰氨基苯基)丙酰胺作为有效的瞬时受体电位香草酸 1（TRPV1）拮抗剂：N-(6-三氟甲基吡啶-3-基甲基)C 区 2-氨基衍生物的结构活性关系。
J Med Chem. 2012 Oct 11;55(19):8392-408. doi: 10.1021/jm300780p. Epub 2012 Sep 20.
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Targeting TRPV1 for pain relief: limits, losers and laurels.针对 TRPV1 缓解疼痛：限制、输家和胜利者。
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Structural insights into transient receptor potential vanilloid type 1 (TRPV1) from homology modeling, flexible docking, and mutational studies.同源建模、柔性对接和突变研究揭示瞬时受体电位香草酸亚型 1（TRPV1）的结构见解。
J Comput Aided Mol Des. 2011 Apr;25(4):317-27. doi: 10.1007/s10822-011-9421-5. Epub 2011 Mar 30.
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Transient receptor potential vanilloid-1 antagonists: a survey of recent patent literature.瞬时受体电位香草酸 1 型拮抗剂：近期专利文献综述。
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Therapeutic potential of vanilloid receptor TRPV1 agonists and antagonists as analgesics: Recent advances and setbacks.香草酸受体TRPV1激动剂和拮抗剂作为镇痛药的治疗潜力：最新进展与挫折
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