(E)-3-{4-[3-(2-tert-butyl-1H-indol-3-yl)piperidin-1-ylmethyl]-3-fluorophenyl}-N-hydroxyacrylamide | 1218929-19-1

• 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: (E)-3-{4-[3-(2-tert-butyl-1H-indol-3-yl)piperidin-1-ylmethyl]-3-fluorophenyl}-N-hydroxyacrylamide
• 英文别名: (E)-3-{4-[(S)-3-(2-tert-butyl-1H-indol-3-yl)piperidin-1-ylmethyl]-3-fluorophenyl}-N-hydroxyacrylamide；(E)-3-[4-[[3-(2-tert-butyl-1H-indol-3-yl)piperidin-1-yl]methyl]-3-fluorophenyl]-N-hydroxyprop-2-enamide
• CAS: 1218929-19-1
• 化学式: C₂₇H₃₂FN₃O₂
• 分子量: 449.568
• InChiKey: ILQPFWGPYWQTHJ-ACCUITESSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.1
• 重原子数：
  33
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.37
• 拓扑面积：
  68.4
• 氢给体数：
  3
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  (E)-3-{4-[3-(2-tert-butyl-1H-indol-3-yl)piperidin-1-ylmethyl]-3-fluorophenyl}acrylic acid methyl ester 在 羟胺 、 sodium methylate 作用下， 以 甲醇 、 水 为溶剂， 反应 2.5h， 以11%的产率得到(E)-3-{4-[3-(2-tert-butyl-1H-indol-3-yl)piperidin-1-ylmethyl]-3-fluorophenyl}-N-hydroxyacrylamide
  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

• Hydroxamate-Based Inhibitors of Deacetylases
  申请人：CHO Young Shin

  公开号：US20110053925A1

  公开（公告）日：2011-03-03

  The present teachings relate to compounds of Formula I: and pharmaceutically acceptable salts, hydrates, esters, and prodrugs thereof, wherein R 1 , R 2 , R 3 , ring A, and are as defined herein. The present teachings also provide methods of preparing compounds of Formula I and methods of using compounds of Formula I in treating, inhibiting, or preventing pathologic conditions or disorders mediated wholly or in part by deacetylases.

  本教导涉及到Formula I的化合物，以及其药用盐、水合物、酯和前药，其中R1、R2、R3、环A和如此定义。本教导还提供了制备Formula I化合物的方法，以及利用Formula I化合物治疗、抑制或预防完全或部分由去乙酰酶介导的病理状况或紊乱的方法。
• 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.