(E)-3-{4-[(3,3-difluoropropylamino)methyl]phenyl}acrylic acid methyl ester | 1312891-71-6

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 肉桂酸及其衍生物
• 英文名称: (E)-3-{4-[(3,3-difluoropropylamino)methyl]phenyl}acrylic acid methyl ester
• 英文别名: methyl (E)-3-[4-[(3,3-difluoropropylamino)methyl]phenyl]prop-2-enoate
• CAS: 1312891-71-6
• 化学式: C₁₄H₁₇F₂NO₂
• 分子量: 269.291
• InChiKey: VLXBJNMIHIWTHO-VOTSOKGWSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  19
• 可旋转键数：
  8
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  38.3
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (E)-3-{4-[(3,3-difluoropropylamino)methyl]phenyl}acrylic acid methyl ester 、 2-(2-methyl-1H-indol-3-yl)acetaldehyde 在 碳酸氢钠 、 三乙酰氧基硼氢化钠 作用下， 以 四氢呋喃 为溶剂， 反应 48.0h， 以74%的产率得到(E)-3-[4-({(3,3-difluoropropyl)[2-(2-methyl-1H-indol-3-yl)ethyl]amino}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
• 作为产物：
  描述：

  (E)-3-(4-醛基苯基)丙烯酸甲酯 、 3,3-二氟丙烷-1-胺盐酸 在 SiliaBond cyanoborohydride 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 0.42h， 以81%的产率得到(E)-3-{4-[(3,3-difluoropropylamino)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

文献信息

• Optimization of the in Vitro Cardiac Safety of Hydroxamate-Based Histone Deacetylase Inhibitors
  作者：Michael D. Shultz、Xueying Cao、Christine H. Chen、Young Shin Cho、Nicole R. Davis、Joe Eckman、Jianmei Fan、Alex Fekete、Brant Firestone、Julie Flynn、Jack Green、Joseph D. Growney、Mats Holmqvist、Meier Hsu、Daniel Jansson、Lei Jiang、Paul Kwon、Gang Liu、Franco Lombardo、Qiang Lu、Dyuti Majumdar、Christopher Meta、Lawrence Perez、Minying Pu、Tim Ramsey、Stacy Remiszewski、Suzanne Skolnik、Martin Traebert、Laszlo Urban、Vinita Uttamsingh、Ping Wang、Steven Whitebread、Lewis Whitehead、Yan Yan-Neale、Yung-Mae Yao、Liping Zhou、Peter Atadja

  DOI：10.1021/jm200388e

  日期：2011.7.14

  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.