3-[1-(4-bromo-2-fluorobenzyl)piperidin-3-yl]-1H-indole | 1218929-05-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌啶类
• 英文名称: 3-[1-(4-bromo-2-fluorobenzyl)piperidin-3-yl]-1H-indole
• 英文别名: 3-[1-[(4-bromo-2-fluorophenyl)methyl]piperidin-3-yl]-1H-indole
• CAS: 1218929-05-5
• 化学式: C₂₀H₂₀BrFN₂
• 分子量: 387.295
• InChiKey: MXMWFHIHGBCOOA-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.9
• 重原子数：
  24
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.3
• 拓扑面积：
  19
• 氢给体数：
  1
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  3-[1-(4-bromo-2-fluorobenzyl)piperidin-3-yl]-1H-indole 、 丙烯酸甲酯（MA） 在 tris-(dibenzylideneacetone)dipalladium(0) 、 tri tert-butylphosphoniumtetrafluoroborate 作用下， 以 1,4-二氧六环 为溶剂， 反应 1.0h， 生成 (E)-3-{3-fluoro-4-[3-(1H-indol-3-yl)piperidin-1-ylmethyl]phenyl}acrylic acid methyl ester
  参考文献：
  名称：

  Conformational Refinement of Hydroxamate-Based Histone Deacetylase Inhibitors and Exploration of 3-Piperidin-3-ylindole Analogues of Dacinostat (LAQ824)

  摘要：

  Inspired by natural product HDAC inhibitors, we prepared a series of conformationally restrained HDAC inhibitors based on the hydroxamic acid dacinostat (LAQ824, 7). Several scaffolds with improved biochemical and cellular potency, as well as attenuated hERG inhibition, were identified, suggesting that the introduction of molecular rigidity is a viable strategy to enhance HDAC binding and mitigate hERG liability. Further SAR studies around a 3-piperidin-3-ylindole moiety resulted in the discovery of compound 30, for which a unique conformation was speculated to contribute to overcoming increased lipophilicity and attenuating h ERG binding. Separation of racemate 30 afforded 32, the R enantiomer, which demonstrated improved potency in both enzyme and cellular assays compared to dacinostat.

  DOI：

  10.1021/jm100007m
• 作为产物：
  描述：

  4-溴-2-氟苄溴 、 3-(哌啶-3-YL)-1H-吲哚 在 三乙胺 作用下， 以 二氯甲烷 为溶剂， 反应 4.0h， 生成 3-[1-(4-bromo-2-fluorobenzyl)piperidin-3-yl]-1H-indole
  参考文献：
  名称：

  Conformational Refinement of Hydroxamate-Based Histone Deacetylase Inhibitors and Exploration of 3-Piperidin-3-ylindole Analogues of Dacinostat (LAQ824)

  摘要：

  Inspired by natural product HDAC inhibitors, we prepared a series of conformationally restrained HDAC inhibitors based on the hydroxamic acid dacinostat (LAQ824, 7). Several scaffolds with improved biochemical and cellular potency, as well as attenuated hERG inhibition, were identified, suggesting that the introduction of molecular rigidity is a viable strategy to enhance HDAC binding and mitigate hERG liability. Further SAR studies around a 3-piperidin-3-ylindole moiety resulted in the discovery of compound 30, for which a unique conformation was speculated to contribute to overcoming increased lipophilicity and attenuating h ERG binding. Separation of racemate 30 afforded 32, the R enantiomer, which demonstrated improved potency in both enzyme and cellular assays compared to dacinostat.

  DOI：

  10.1021/jm100007m

文献信息

• Conformational Refinement of Hydroxamate-Based Histone Deacetylase Inhibitors and Exploration of 3-Piperidin-3-ylindole Analogues of Dacinostat (LAQ824)
  作者：Young Shin Cho、Lewis Whitehead、Jianke Li、Christine H.-T. Chen、Lei Jiang、Markus Vögtle、Eric Francotte、Paul Richert、Trixie Wagner、Martin Traebert、Qiang Lu、Xueying Cao、Berengere Dumotier、Jasna Fejzo、Srinivasan Rajan、Ping Wang、Yan Yan-Neale、Wenlin Shao、Peter Atadja、Michael Shultz

  DOI：10.1021/jm100007m

  日期：2010.4.8

  Inspired by natural product HDAC inhibitors, we prepared a series of conformationally restrained HDAC inhibitors based on the hydroxamic acid dacinostat (LAQ824, 7). Several scaffolds with improved biochemical and cellular potency, as well as attenuated hERG inhibition, were identified, suggesting that the introduction of molecular rigidity is a viable strategy to enhance HDAC binding and mitigate hERG liability. Further SAR studies around a 3-piperidin-3-ylindole moiety resulted in the discovery of compound 30, for which a unique conformation was speculated to contribute to overcoming increased lipophilicity and attenuating h ERG binding. Separation of racemate 30 afforded 32, the R enantiomer, which demonstrated improved potency in both enzyme and cellular assays compared to dacinostat.