Ethyl 3-[3-tert-butylsulfanyl-5-(pyridin-2-ylmethoxy)-1-[(4-pyrimidin-5-ylphenyl)methyl]indol-2-yl]-2,2-dimethylpropanoate | 1190361-80-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 英文名称: Ethyl 3-[3-tert-butylsulfanyl-5-(pyridin-2-ylmethoxy)-1-[(4-pyrimidin-5-ylphenyl)methyl]indol-2-yl]-2,2-dimethylpropanoate
• CAS: 1190361-80-8
• 化学式: C₃₆H₄₀N₄O₃S
• 分子量: 608.805
• InChiKey: PKGUSDLGWWLJSO-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.8
• 重原子数：
  44
• 可旋转键数：
  13
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  104
• 氢给体数：
  0
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  Ethyl 3-[3-tert-butylsulfanyl-5-(pyridin-2-ylmethoxy)-1-[(4-pyrimidin-5-ylphenyl)methyl]indol-2-yl]-2,2-dimethylpropanoate 在 水 、 lithium hydroxide 作用下， 以 四氢呋喃 、 甲醇 为溶剂， 反应 4.0h， 生成 3-[3-tert-butylsulfanyl-5-(pyridin-2-ylmethoxy)-1-(4-pyrimidin-5-yl-benzyl)-1H-indol-2-yl]-2,2-dimethyl-propionic acid
  参考文献：
  名称：

  5-Lipoxygenase-Activating Protein Inhibitors: Development of 3-[3-tert-Butylsulfanyl-1-[4-(6-methoxy-pyridin-3-yl)-benzyl]-5-(pyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic Acid (AM103)

  摘要：

  The potent and selective 5-lipoxygenase-activating protein leukotriene synthesis inhibitor 3-[3-tert-butyl-sulfanyl-1-[4-(6-methoxy-pyridin-3-yl)-benzyl]-5-(pyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethylpropionic acid (11j) is described. Lead optimization was designed to afford compounds with superior in vitro and in vivo inhibition of leukotriene synthesis in addition to having excellent pharmacokinetics and safety in rats and dogs. The key structural features of these new compounds are incorporation of heterocycles on the indole N-benzyl substituent and replacement of the quinoline group resulting in compounds with excellent in vitro and in vim activities, superior pharmacokinetics, and improved physical properties. The methoxypyridine derivative 11j has an IC50 of 4.2 nM in a 5-lipoxygenase-activating protein (FLAP) binding assay, an IC50 of 349 nM in the human blood LTB4 inhibition assay, and is efficacious in a murine ovalbumin model of allergen-induced asthma. Compound 11j was selected for clinical development and has successfully completed phase I trials in healthy volunteers.

  DOI：

  10.1021/jm900945d
• 作为产物：
  描述：

  1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl-3-[3-tert-butylsulfanyl-5-(pyridine-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic acid ethyl ester 、 alkaline earth salt of/the/ methylsulfuric acid 在 四(三苯基膦)钯 、 potassium carbonate 作用下， 以 乙二醇二甲醚 、 水 为溶剂， 生成 Ethyl 3-[3-tert-butylsulfanyl-5-(pyridin-2-ylmethoxy)-1-[(4-pyrimidin-5-ylphenyl)methyl]indol-2-yl]-2,2-dimethylpropanoate
  参考文献：
  名称：

  5-Lipoxygenase-Activating Protein Inhibitors: Development of 3-[3-tert-Butylsulfanyl-1-[4-(6-methoxy-pyridin-3-yl)-benzyl]-5-(pyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic Acid (AM103)

  摘要：

  The potent and selective 5-lipoxygenase-activating protein leukotriene synthesis inhibitor 3-[3-tert-butyl-sulfanyl-1-[4-(6-methoxy-pyridin-3-yl)-benzyl]-5-(pyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethylpropionic acid (11j) is described. Lead optimization was designed to afford compounds with superior in vitro and in vivo inhibition of leukotriene synthesis in addition to having excellent pharmacokinetics and safety in rats and dogs. The key structural features of these new compounds are incorporation of heterocycles on the indole N-benzyl substituent and replacement of the quinoline group resulting in compounds with excellent in vitro and in vim activities, superior pharmacokinetics, and improved physical properties. The methoxypyridine derivative 11j has an IC50 of 4.2 nM in a 5-lipoxygenase-activating protein (FLAP) binding assay, an IC50 of 349 nM in the human blood LTB4 inhibition assay, and is efficacious in a murine ovalbumin model of allergen-induced asthma. Compound 11j was selected for clinical development and has successfully completed phase I trials in healthy volunteers.

  DOI：

  10.1021/jm900945d

文献信息

• 5-Lipoxygenase-Activating Protein Inhibitors: Development of 3-[3-<i>tert</i>-Butylsulfanyl-1-[4-(6-methoxy-pyridin-3-yl)-benzyl]-5-(pyridin-2-ylmethoxy)-1<i>H</i>-indol-2-yl]-2,2-dimethyl-propionic Acid (AM103)
  作者：John H. Hutchinson、Yiwei Li、Jeannie M. Arruda、Christopher Baccei、Gretchen Bain、Charles Chapman、Lucia Correa、Janice Darlington、Christopher D. King、Catherine Lee、Dan Lorrain、Pat Prodanovich、Haojing Rong、Angelina Santini、Nicholas Stock、Peppi Prasit、Jilly F. Evans

  DOI：10.1021/jm900945d

  日期：2009.10.8

  The potent and selective 5-lipoxygenase-activating protein leukotriene synthesis inhibitor 3-[3-tert-butyl-sulfanyl-1-[4-(6-methoxy-pyridin-3-yl)-benzyl]-5-(pyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethylpropionic acid (11j) is described. Lead optimization was designed to afford compounds with superior in vitro and in vivo inhibition of leukotriene synthesis in addition to having excellent pharmacokinetics and safety in rats and dogs. The key structural features of these new compounds are incorporation of heterocycles on the indole N-benzyl substituent and replacement of the quinoline group resulting in compounds with excellent in vitro and in vim activities, superior pharmacokinetics, and improved physical properties. The methoxypyridine derivative 11j has an IC50 of 4.2 nM in a 5-lipoxygenase-activating protein (FLAP) binding assay, an IC50 of 349 nM in the human blood LTB4 inhibition assay, and is efficacious in a murine ovalbumin model of allergen-induced asthma. Compound 11j was selected for clinical development and has successfully completed phase I trials in healthy volunteers.