1-(6-methoxypyrid-3-yl)benzyl-3-[3-tert-butylsulfoxide-5-(hydroxy)-1H-indol-2-yl]-2,2-dimethyl-propionic acid ethyl ester

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶及其衍生物
• 英文名称: 1-(6-methoxypyrid-3-yl)benzyl-3-[3-tert-butylsulfoxide-5-(hydroxy)-1H-indol-2-yl]-2,2-dimethyl-propionic acid ethyl ester
• 英文别名: Ethyl 3-[3-tert-butylsulfinyl-5-hydroxy-1-[[4-(6-methoxypyridin-3-yl)phenyl]methyl]indol-2-yl]-2,2-dimethylpropanoate
• 化学式: C₃₂H₃₈N₂O₅S
• 分子量: 562.73
• InChiKey: BIRLZBBWZVKKCA-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.5
• 重原子数：
  40
• 可旋转键数：
  11
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  110
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  1-(6-methoxypyrid-3-yl)benzyl-3-[3-tert-butylsulfoxide-5-(hydroxy)-1H-indol-2-yl]-2,2-dimethyl-propionic acid ethyl ester 、 2-氯甲基吡啶盐酸盐 在 四丁基溴化铵 、 caesium carbonate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 以50 mg的产率得到Ethyl 3-[3-tert-butylsulfinyl-1-[[4-(6-methoxypyridin-3-yl)phenyl]methyl]-5-(pyridin-2-ylmethoxy)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
• 作为产物：
  描述：

  3-{3-tert-butylsulfanyl-5-hydroxy-1-[4-(6-methoxy-pyridin-3-yl)-benzyl]-1H-indol-2-yl}-2,2-dimethyl-propionic acid ethyl ester 在 间氯过氧苯甲酸 作用下， 以 二氯甲烷 为溶剂， 反应 0.25h， 以60 mg的产率得到1-(6-methoxypyrid-3-yl)benzyl-3-[3-tert-butylsulfoxide-5-(hydroxy)-1H-indol-2-yl]-2,2-dimethyl-propionic acid ethyl ester
  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.