5-chloro-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methyl-N-((4-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzamide

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 5-chloro-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methyl-N-((4-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzamide
• 英文别名: 5-chloro-3-[ethyl(oxan-4-yl)amino]-2-methyl-N-[(4-methyl-2-oxo-1H-pyridin-3-yl)methyl]benzamide
• 化学式: C₂₂H₂₈ClN₃O₃
• 分子量: 417.936
• InChiKey: BLMJHGTVAAFFQJ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.3
• 重原子数：
  29
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.45
• 拓扑面积：
  70.7
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  5-氯-2-甲基-3-硝基苯甲酸 在 benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate 、 铁粉 、 sodium cyanoborohydride 、 sodium carbonate 、 氯化铵 、 caesium carbonate 、 溶剂黄146 、 sodium hydroxide 作用下， 以 甲醇 、 乙醇 、 水 、 溶剂黄146 、 二甲基亚砜 、 N,N-二甲基甲酰胺 为溶剂， 反应 11.0h， 生成 5-chloro-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methyl-N-((4-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzamide
  参考文献：
  名称：

  The Importance of Being Me: Magic Methyls, Methyltransferase Inhibitors, and the Discovery of Tazemetostat

  摘要：

  Posttranslational methylation of histones plays a critical role in gene regulation. Misregulation of histone methylation can lead to oncogenic transformation. Enhancer of Zeste homologue 2 (EZH2) methylates histone 3 at lysine 27 (H3K27) and abnormal methylation of this site is found in many cancers. Tazemetostat, an EHZ2 inhibitor in clinical development, has shown activity in both preclinical models of cancer as well as in patients with lymphoma or INI1-deficient solid tumors. Herein we report the structure activity relationships from identification of an initial hit in a high-throughput screen through selection of tazemetostat for clinical development. The importance of several methyl groups to the potency of the inhibitors is highlighted as well as the importance of balancing pharmacokinetic properties with potency.

  DOI：

  10.1021/acs.jmedchem.5b01501

文献信息

• [EN] SUBSTITUTED BENZENE COMPOUNDS<br/>[FR] COMPOSÉS DE BENZÈNES SUBSTITUÉS
  申请人：EPIZYME INC

  公开号：WO2012142513A1

  公开（公告）日：2012-10-18

  The present invention relates to substituted benzene compounds. The present invention also relates to pharmaceutical compositions containing these compounds and methods of treating cancer by administering these compounds and pharmaceutical compositions to subjects in need thereof. The present invention also relates to the use of such compounds for research or other non-therapeutic purposes.

  本发明涉及取代苯化合物。本发明还涉及含有这些化合物的药物组合物，以及通过向需要的受试者投与这些化合物和药物组合物来治疗癌症的方法。本发明还涉及利用这些化合物进行研究或其他非治疗目的的用途。
• Substituted Benzene Compounds
  申请人：Kuntz Kevin Wayne

  公开号：US20140142083A1

  公开（公告）日：2014-05-22

  The present invention relates to substituted benzene compounds. The present invention also relates to pharmaceutical compositions containing these compounds and methods of treating cancer by administering these compounds and pharmaceutical compositions to subjects in need thereof. The present invention also relates to the use of such compounds for research or other non-therapeutic purposes.

  本发明涉及取代苯化合物。本发明还涉及含有这些化合物的制药组合物以及通过将这些化合物和制药组合物用于需要治疗的受试者的方法来治疗癌症。本发明还涉及将这些化合物用于研究或其他非治疗目的的使用。
• SUBSTITUTED BENZENE COMPOUNDS
  申请人：Epizyme, Inc.

  公开号：EP2697198B1

  公开（公告）日：2016-06-08
• US9376422B2
  申请人：——

  公开号：US9376422B2

  公开（公告）日：2016-06-28
• The Importance of Being Me: Magic Methyls, Methyltransferase Inhibitors, and the Discovery of Tazemetostat
  作者：Kevin W. Kuntz、John E. Campbell、Heike Keilhack、Roy M. Pollock、Sarah K. Knutson、Margaret Porter-Scott、Victoria M. Richon、Chris J. Sneeringer、Tim J. Wigle、Christina J. Allain、Christina R. Majer、Mikel P. Moyer、Robert A. Copeland、Richard Chesworth

  DOI：10.1021/acs.jmedchem.5b01501

  日期：2016.2.25

  Posttranslational methylation of histones plays a critical role in gene regulation. Misregulation of histone methylation can lead to oncogenic transformation. Enhancer of Zeste homologue 2 (EZH2) methylates histone 3 at lysine 27 (H3K27) and abnormal methylation of this site is found in many cancers. Tazemetostat, an EHZ2 inhibitor in clinical development, has shown activity in both preclinical models of cancer as well as in patients with lymphoma or INI1-deficient solid tumors. Herein we report the structure activity relationships from identification of an initial hit in a high-throughput screen through selection of tazemetostat for clinical development. The importance of several methyl groups to the potency of the inhibitors is highlighted as well as the importance of balancing pharmacokinetic properties with potency.