[2-Benzyl-3-[(4-hydroxy-3-methoxyphenyl)methylcarbamothioylamino]propyl] hexanoate

• 分子结构分类: 有机化合物 - 苯类化合物 - 酚类
• 英文名称: [2-Benzyl-3-[(4-hydroxy-3-methoxyphenyl)methylcarbamothioylamino]propyl] hexanoate
• 化学式: C₂₅H₃₄N₂O₄S
• 分子量: 458.622
• InChiKey: HJYMIQRVVGUXNB-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.1
• 重原子数：
  32
• 可旋转键数：
  14
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.44
• 拓扑面积：
  112
• 氢给体数：
  3
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  苄基丙二酸二乙酯 在 Lindlar's catalyst 4-二甲氨基吡啶 、 lithium aluminium tetrahydride 、 sodium azide 、 氢气 、 potassium carbonate 、 对甲苯磺酸 、 三乙胺 、 三氟乙酸 作用下， 以 甲醇 、 乙醚 、 乙醇 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 24.0h， 生成 [2-Benzyl-3-[(4-hydroxy-3-methoxyphenyl)methylcarbamothioylamino]propyl] hexanoate
  参考文献：
  名称：

  N-(3-acyloxy-2-benzylpropyl)-N′-(4-hydroxy-3-methoxybenzyl)thiourea derivatives as potent vanilloid receptor agonists and analgesics

  摘要：

  A series of N-(3-acyloxy-2-benzylpropyl)-N'-(4-hydroxy-3-methoxybenzyl)thioura derivatives were investigated as vanilloid receptor ligands in an effort to discover a novel class of analgesics. The proposed pharmacophore model of resiniferatoxin, which includes the C-20-homovanillic moiety, the C-3-carbonyl and the orthoester phenyl ring as key pharmacophoric groups, was utilized as a guide for drug design. The compounds were synthesized after several steps from diethylmalonate and evaluated in vitro in a receptor binding assay and in a capsaicin-activated channel assay. Additional evaluation of analgesic activity, anti-inflammatory activity and pungency was conducted in animal models by the writhing test, the ear edema assay, and the eye-wiping test, respectively. Among the new compounds, 23 and 28 were found to be the most potent receptor agonists of the series with K-i values of 19 nM and 11 nM, respectively. Their strong in vitro potencies were also reflected by an excellent analgesic profile in animal tests with ED50 values of 0.5 mug/kg for 23 and 1.0 mug/kg for 28. Relative to capsaicin these compounds appear to be ca. 600 and 300 times more potent. Both 23 and 28 were found to be less pungent than capsaicin based on the eye-wiping test. However, the compounds did not show significant anti-inflammatory activity. A molecular modeling study comparing the energy-minimized structures of resiniferatoxin and 35 demonstrated a good correlation in the spatial disposition of the corresponding key pharmacophores. The thioureas described in this investigation, which were designed as simplified resiniferatoxin surrogates, represent a novel class of potent vanilloid receptor agonists endowed with potent analgesic activity and reduced pungency. (C) 2000 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0968-0896(00)00216-9

文献信息

• N-(3-acyloxy-2-benzylpropyl)-N′-(4-hydroxy-3-methoxybenzyl)thiourea derivatives as potent vanilloid receptor agonists and analgesics
  作者：Jeewoo Lee、Jiyoun Lee、Jiyoung Kim、Soo Yeon Kim、Moon Woo Chun、Hawon Cho、Sun Wook Hwang、Uhtaek Oh、Young Ho Park、Victor E Marquez、Maryam Beheshti、Tamas Szabo、Peter M Blumberg

  DOI：10.1016/s0968-0896(00)00216-9

  日期：2001.1

  A series of N-(3-acyloxy-2-benzylpropyl)-N'-(4-hydroxy-3-methoxybenzyl)thioura derivatives were investigated as vanilloid receptor ligands in an effort to discover a novel class of analgesics. The proposed pharmacophore model of resiniferatoxin, which includes the C-20-homovanillic moiety, the C-3-carbonyl and the orthoester phenyl ring as key pharmacophoric groups, was utilized as a guide for drug design. The compounds were synthesized after several steps from diethylmalonate and evaluated in vitro in a receptor binding assay and in a capsaicin-activated channel assay. Additional evaluation of analgesic activity, anti-inflammatory activity and pungency was conducted in animal models by the writhing test, the ear edema assay, and the eye-wiping test, respectively. Among the new compounds, 23 and 28 were found to be the most potent receptor agonists of the series with K-i values of 19 nM and 11 nM, respectively. Their strong in vitro potencies were also reflected by an excellent analgesic profile in animal tests with ED50 values of 0.5 mug/kg for 23 and 1.0 mug/kg for 28. Relative to capsaicin these compounds appear to be ca. 600 and 300 times more potent. Both 23 and 28 were found to be less pungent than capsaicin based on the eye-wiping test. However, the compounds did not show significant anti-inflammatory activity. A molecular modeling study comparing the energy-minimized structures of resiniferatoxin and 35 demonstrated a good correlation in the spatial disposition of the corresponding key pharmacophores. The thioureas described in this investigation, which were designed as simplified resiniferatoxin surrogates, represent a novel class of potent vanilloid receptor agonists endowed with potent analgesic activity and reduced pungency. (C) 2000 Elsevier Science Ltd. All rights reserved.