2-(4-(cyclohexylmethyl)-1,4-diazepan-1-yl)-N-(1-isopropylpiperidin-4-yl)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-amine | 1320288-54-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二氮杂萘
• 英文名称: 2-(4-(cyclohexylmethyl)-1,4-diazepan-1-yl)-N-(1-isopropylpiperidin-4-yl)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-amine
• 英文别名: 2-[4-(cyclohexylmethyl)-1,4-diazepan-1-yl]-6-methoxy-N-(1-propan-2-ylpiperidin-4-yl)-7-(3-pyrrolidin-1-ylpropoxy)quinazolin-4-amine
• CAS: 1320288-54-7
• 化学式: C₃₆H₅₉N₇O₂
• 分子量: 621.91
• InChiKey: VBRFDVRFFMPWPY-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  7.1
• 重原子数：
  45
• 可旋转键数：
  12
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.78
• 拓扑面积：
  69.2
• 氢给体数：
  1
• 氢受体数：
  9

反应信息

• 作为产物：
  描述：

  苯甲酸,4-(3-氯丙氧基)-3-甲氧基-,甲基酯 在 ammonium acetate 、 水 、 硝酸 、 乙酸酐 、 四丁基碘化铵 、 铁粉 、 potassium carbonate 、 溶剂黄146 、 N,N-二异丙基乙胺 、 三氟乙酸 、 N,N-二乙基苯胺 、 sodium iodide 、 sodium hydroxide 、 三氯氧磷 作用下， 以 四氢呋喃 、 甲醇 、 水 、 乙酸乙酯 、 异丙醇 、 乙腈 为溶剂， 反应 10.25h， 生成 2-(4-(cyclohexylmethyl)-1,4-diazepan-1-yl)-N-(1-isopropylpiperidin-4-yl)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-amine
  参考文献：
  名称：

  Optimization of Cellular Activity of G9a Inhibitors 7-Aminoalkoxy-quinazolines

  摘要：

  Protein lysine methyltransferase G9a plays key roles in the transcriptional repression of a variety of genes via dimethylation of lysine 9 on histone H3 (H3K9me2) of chromatin as well as dimethylation of nonhistone proteins including tumor suppressor p53. We previously reported the discovery of UNC0321 (3), the most potent G9a inhibitor to date, via structure-based design and structure-activity relationship (SAR) exploration of the quinazoline scaffold represented by BIX01294 (1). Despite its very high in vitro potency, compound 3 lacks sufficient cellular potency. The design and synthesis of several generations of new analogues aimed at improving cell membrane permeability while maintaining high in vitro potency resulted in the discovery of a number of novel G9a inhibitors such as UNC0646 (6) and UNC0631 (7) with excellent potency in a variety of cell lines and excellent separation of functional potency versus cell toxicity. The design, synthesis, and cellular SAR of these potent G9a inhibitors are described.

  DOI：

  10.1021/jm200903z

文献信息

• Optimization of Cellular Activity of G9a Inhibitors 7-Aminoalkoxy-quinazolines
  作者：Feng Liu、Dalia Barsyte-Lovejoy、Abdellah Allali-Hassani、Yunlong He、J. Martin Herold、Xin Chen、Christopher M. Yates、Stephen V. Frye、Peter J. Brown、Jing Huang、Masoud Vedadi、Cheryl H. Arrowsmith、Jian Jin

  DOI：10.1021/jm200903z

  日期：2011.9.8

  Protein lysine methyltransferase G9a plays key roles in the transcriptional repression of a variety of genes via dimethylation of lysine 9 on histone H3 (H3K9me2) of chromatin as well as dimethylation of nonhistone proteins including tumor suppressor p53. We previously reported the discovery of UNC0321 (3), the most potent G9a inhibitor to date, via structure-based design and structure-activity relationship (SAR) exploration of the quinazoline scaffold represented by BIX01294 (1). Despite its very high in vitro potency, compound 3 lacks sufficient cellular potency. The design and synthesis of several generations of new analogues aimed at improving cell membrane permeability while maintaining high in vitro potency resulted in the discovery of a number of novel G9a inhibitors such as UNC0646 (6) and UNC0631 (7) with excellent potency in a variety of cell lines and excellent separation of functional potency versus cell toxicity. The design, synthesis, and cellular SAR of these potent G9a inhibitors are described.