1-[(1R)-1-[4-[3-(cyclopropoxy)azetidin-1-yl]cyclohexyl]ethyl]-5-fluoro-2-methyl-N-[(6-methyl-4-methylsulfanyl-2-oxo-1H-pyridin-3-yl)methyl]pyrrolo[2,3-b]pyridine-3-carboxamide

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯并吡啶类
• 英文名称: 1-[(1R)-1-[4-[3-(cyclopropoxy)azetidin-1-yl]cyclohexyl]ethyl]-5-fluoro-2-methyl-N-[(6-methyl-4-methylsulfanyl-2-oxo-1H-pyridin-3-yl)methyl]pyrrolo[2,3-b]pyridine-3-carboxamide
• 化学式: C₃₁H₄₀FN₅O₃S
• 分子量: 581.755
• InChiKey: WSDDOMRMKDVMND-SYYKKAFVSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.12
• 重原子数：
  41.0
• 可旋转键数：
  9.0
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.58
• 拓扑面积：
  92.25
• 氢给体数：
  2.0
• 氢受体数：
  7.0

反应信息

• 作为产物：
  描述：

  (R)-(+)-1-(4-甲氧基苯)乙胺 在 2-吡啶甲酸 、 platinum(IV) oxide 、 copper(l) iodide 、 水 、 氢溴酸 、 氢气 、 potassium carbonate 、 caesium carbonate 、 戴斯-马丁氧化剂 、 溶剂黄146 、 N,N-二异丙基乙胺 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 、 potassium iodide 、 sodium hydroxide 作用下， 以 甲醇 、 乙醇 、 二氯甲烷 、 水 、 溶剂黄146 、 N,N-二甲基甲酰胺 为溶剂， -70.0~150.0 ℃ 、379.22 kPa 条件下， 反应 135.5h， 生成 1-[(1R)-1-[4-[3-(cyclopropoxy)azetidin-1-yl]cyclohexyl]ethyl]-5-fluoro-2-methyl-N-[(6-methyl-4-methylsulfanyl-2-oxo-1H-pyridin-3-yl)methyl]pyrrolo[2,3-b]pyridine-3-carboxamide
  参考文献：
  名称：

  Design, Synthesis, and Pharmacological Evaluation of Second Generation EZH2 Inhibitors with Long Residence Time

  摘要：

  Histone methyltransferase EZH2, which is the catalytic subunit of the PRC2 complex, catalyzes the methylation of histone H3K27-a transcriptionally repressive post-translational modification (PTM). EZH2 is commonly mutated in hematologic malignancies and frequently overexpressed in solid tumors, where its expression level often correlates with poor prognosis. First generation EZH2 inhibitors are beginning to show clinical benefit, and we believe that a second generation EZH2 inhibitor could further build upon this foundation to fully realize the therapeutic potential of EZH2 inhibition. During our medicinal chemistry campaign, we identified 4-thiomethyl pyridone as a key modification that led to significantly increased potency and prolonged residence time. Leveraging this finding, we optimized a series of EZH2 inhibitors, with enhanced antitumor activity and improved physiochemical properties, which have the potential to expand the clinical use of EZH2 inhibition.

  DOI：

  10.1021/acsmedchemlett.0c00045

文献信息

• Design, Synthesis, and Pharmacological Evaluation of Second Generation EZH2 Inhibitors with Long Residence Time
  作者：Avinash Khanna、Alexandre Côté、Shilpi Arora、Ludivine Moine、Victor S. Gehling、Jehrod Brenneman、Nico Cantone、Jacob I. Stuckey、Shruti Apte、Ashwin Ramakrishnan、Kamil Bruderek、William D. Bradley、James E. Audia、Richard T. Cummings、Robert J. Sims、Patrick Trojer、Julian R. Levell

  DOI：10.1021/acsmedchemlett.0c00045

  日期：2020.6.11

  Histone methyltransferase EZH2, which is the catalytic subunit of the PRC2 complex, catalyzes the methylation of histone H3K27-a transcriptionally repressive post-translational modification (PTM). EZH2 is commonly mutated in hematologic malignancies and frequently overexpressed in solid tumors, where its expression level often correlates with poor prognosis. First generation EZH2 inhibitors are beginning to show clinical benefit, and we believe that a second generation EZH2 inhibitor could further build upon this foundation to fully realize the therapeutic potential of EZH2 inhibition. During our medicinal chemistry campaign, we identified 4-thiomethyl pyridone as a key modification that led to significantly increased potency and prolonged residence time. Leveraging this finding, we optimized a series of EZH2 inhibitors, with enhanced antitumor activity and improved physiochemical properties, which have the potential to expand the clinical use of EZH2 inhibition.