(E)-3-[4-({2-[2-(3,5-dimethylisoxazol-4-yl)-1H-indol-3-yl]ethylamino}methyl)phenyl]acrylic acid methyl ester | 1312891-83-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 英文名称: (E)-3-[4-({2-[2-(3,5-dimethylisoxazol-4-yl)-1H-indol-3-yl]ethylamino}methyl)phenyl]acrylic acid methyl ester
• 英文别名: methyl (E)-3-[4-[[2-[2-(3,5-dimethyl-1,2-oxazol-4-yl)-1H-indol-3-yl]ethylamino]methyl]phenyl]prop-2-enoate
• CAS: 1312891-83-0
• 化学式: C₂₆H₂₇N₃O₃
• 分子量: 429.519
• InChiKey: MJXREYVTSGQDMU-OUKQBFOZSA-N

物化性质

• 沸点：
  639.0±55.0 °C(Predicted)
• 密度：
  1.208±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4.6
• 重原子数：
  32
• 可旋转键数：
  9
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.23
• 拓扑面积：
  80.2
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (E)-3-[4-({2-[2-(3,5-dimethylisoxazol-4-yl)-1H-indol-3-yl]ethylamino}methyl)phenyl]acrylic acid methyl ester 、 三氟乙酸 在 羟胺 、 sodium methylate 作用下， 以 甲醇 、 水 为溶剂， 以80%的产率得到(E)-3-[4-({2-[2-(3,5-dimethylisoxazol-4-yl)-1H-indol-3-yl]ethylamino}methyl)phenyl]-N-hydroxy-acrylamide trifluoroacitic acide salt
  参考文献：
  名称：

  Optimization of the in Vitro Cardiac Safety of Hydroxamate-Based Histone Deacetylase Inhibitors

  摘要：

  Histone deacetylase (HDAC) inhibitors have shown promise in treating various forms of cancer. However, many HDAC inhibitors from diverse structural classes have been associated with QT prolongation in humans. Inhibition of the human ether a-go-go related gene (hERG) channel has been associated with QT prolongation and fatal arrhythmias. To determine if the observed cardiac effects of HDAC inhibitors in humans is due to hERG blockade, a highly potent HDAC inhibitor devoid of hERG activity was required. Starting with dacinostat (LAQ824), a highly potent. HDAC inhibitor, we explored the SAR to determine the pharmacophores required for HDAC and hERG inhibition. We disclose here the results of these efforts where a high degree, of pharmacophore homology between these two targets was discovered. This, similarity prevented traditional strategies for mitigating hERG binding/modulation from being successful and novel approaches for reducing hERG inhibition were required. Using a hERG homology model, two compounds, 11r and 25i, were discovered to be highly efficacious with weak affinity for the hERG and other ion channels.

  DOI：

  10.1021/jm200388e
• 作为产物：
  描述：

  吲哚-3-乙腈 在 potassium fluoride 、 tris-(dibenzylideneacetone)dipalladium(0) 、 N-溴代丁二酰亚胺(NBS) 、 硼烷四氢呋喃络合物 、 碳酸氢钠 、 tri tert-butylphosphoniumtetrafluoroborate 作用下， 以 四氢呋喃 、 二氯甲烷 、 甲苯 为溶剂， 反应 69.5h， 生成 (E)-3-[4-({2-[2-(3,5-dimethylisoxazol-4-yl)-1H-indol-3-yl]ethylamino}methyl)phenyl]acrylic acid methyl ester
  参考文献：
  名称：

  Optimization of the in Vitro Cardiac Safety of Hydroxamate-Based Histone Deacetylase Inhibitors

  摘要：

  Histone deacetylase (HDAC) inhibitors have shown promise in treating various forms of cancer. However, many HDAC inhibitors from diverse structural classes have been associated with QT prolongation in humans. Inhibition of the human ether a-go-go related gene (hERG) channel has been associated with QT prolongation and fatal arrhythmias. To determine if the observed cardiac effects of HDAC inhibitors in humans is due to hERG blockade, a highly potent HDAC inhibitor devoid of hERG activity was required. Starting with dacinostat (LAQ824), a highly potent. HDAC inhibitor, we explored the SAR to determine the pharmacophores required for HDAC and hERG inhibition. We disclose here the results of these efforts where a high degree, of pharmacophore homology between these two targets was discovered. This, similarity prevented traditional strategies for mitigating hERG binding/modulation from being successful and novel approaches for reducing hERG inhibition were required. Using a hERG homology model, two compounds, 11r and 25i, were discovered to be highly efficacious with weak affinity for the hERG and other ion channels.

  DOI：

  10.1021/jm200388e