2-{1-[2,6-Dichloro-4-(3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-phenyl]-1-methyl-ethyl}-4-phenyl-thiazole-5-carboxylic acid allyl ester

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 2-{1-[2,6-Dichloro-4-(3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-phenyl]-1-methyl-ethyl}-4-phenyl-thiazole-5-carboxylic acid allyl ester
• 英文别名: Prop-2-enyl 2-[2-[2,6-dichloro-4-(3,5-dioxo-1,2,4-triazin-2-yl)phenyl]propan-2-yl]-4-phenyl-1,3-thiazole-5-carboxylate
• 化学式: C₂₅H₂₀Cl₂N₄O₄S
• 分子量: 543.43
• InChiKey: AODDWOPWEYSTDS-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.4
• 重原子数：
  36
• 可旋转键数：
  8
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.16
• 拓扑面积：
  129
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  3-氧代-3-苯基丙酸叔丁酯 在 溴 、 碳酸氢钠 、 potassium carbonate 、 三氟乙酸 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 反应 11.17h， 生成 2-{1-[2,6-Dichloro-4-(3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-phenyl]-1-methyl-ethyl}-4-phenyl-thiazole-5-carboxylic acid allyl ester
  参考文献：
  名称：

  Synthesis and Biological Evaluation of 1,2,4-Triazinylphenylalkylthiazolecarboxylic Acid Esters as Cytokine-Inhibiting Antedrugs with Strong Bronchodilating Effects in an Animal Model of Asthma

  摘要：

  The influx of leukocytes (eosinophils, lymphocytes, and monocytes) into the airways and their production of proinflammatory cytokines contribute to the severity of allergic asthma. We describe here the synthesis and pharmacological evaluation of a series of triazinylphenylalkyl-thiazolecarboxylic acid esters that were designed to act as lung-specific antedrugs and inhibitors of the production of interleukin (IL)-5, a primary eosinophil-activating and proinflammatory cytokine. Closer examination of the hydroxypropyl ester, 15, indicated its high metabolic stability (t(1/2) > 240 min) in human lung S9 fraction but rapid conversion (t(1/2) = 15 min) into the pharmacologically inactive carboxylic acid by human liver preparations. In stimulated human whole blood cultures, 15 reduced not only the production of IL-5 (IC50 = 78 nM) but also the biosynthesis of the monocyte chemotactic proteins MCP-1 (IC50 = 220 nM), MCP-2 (IC50 = 580 nM), and MCP-3 (IC50 = 80 nM). In vivo, intratracheal administration of 15 (6 mg/animal) to allergic sheep, either before (-4 h) or after (+1.5 h) the pulmonary allergen challenge, completely abrogated the late-phase airway response and reduced the bronchial hyperreactivity to inhaled carbachol.

  DOI：

  10.1021/jm049479m

文献信息

• Synthesis and Biological Evaluation of 1,2,4-Triazinylphenylalkylthiazolecarboxylic Acid Esters as Cytokine-Inhibiting Antedrugs with Strong Bronchodilating Effects in an Animal Model of Asthma
  作者：Eddy J. Freyne、Jean F. Lacrampe、Frederik Deroose、Gustaaf M. Boeckx、Marc Willems、Werner Embrechts、Erwin Coesemans、Johan J. Willems、Jerome M. Fortin、Yannick Ligney、Lieve L. Dillen、Willy F. Cools、Jan Goossens、David Corens、Alex De Groot、Jean P. Van Wauwe

  DOI：10.1021/jm049479m

  日期：2005.3.1

  The influx of leukocytes (eosinophils, lymphocytes, and monocytes) into the airways and their production of proinflammatory cytokines contribute to the severity of allergic asthma. We describe here the synthesis and pharmacological evaluation of a series of triazinylphenylalkyl-thiazolecarboxylic acid esters that were designed to act as lung-specific antedrugs and inhibitors of the production of interleukin (IL)-5, a primary eosinophil-activating and proinflammatory cytokine. Closer examination of the hydroxypropyl ester, 15, indicated its high metabolic stability (t(1/2) > 240 min) in human lung S9 fraction but rapid conversion (t(1/2) = 15 min) into the pharmacologically inactive carboxylic acid by human liver preparations. In stimulated human whole blood cultures, 15 reduced not only the production of IL-5 (IC50 = 78 nM) but also the biosynthesis of the monocyte chemotactic proteins MCP-1 (IC50 = 220 nM), MCP-2 (IC50 = 580 nM), and MCP-3 (IC50 = 80 nM). In vivo, intratracheal administration of 15 (6 mg/animal) to allergic sheep, either before (-4 h) or after (+1.5 h) the pulmonary allergen challenge, completely abrogated the late-phase airway response and reduced the bronchial hyperreactivity to inhaled carbachol.