N-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-2-(4-((6-(methylamino)pyrimidin-4-yl)oxy)phenyl)acetamide

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: N-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-2-(4-((6-(methylamino)pyrimidin-4-yl)oxy)phenyl)acetamide
• 英文别名: N-[4-[(4-ethylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]-2-[4-[6-(methylamino)pyrimidin-4-yl]oxyphenyl]acetamide
• 化学式: C₂₇H₃₁F₃N₆O₂
• 分子量: 528.577
• InChiKey: RXTNVGURVJDDNQ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.1
• 重原子数：
  38
• 可旋转键数：
  9
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.37
• 拓扑面积：
  82.6
• 氢给体数：
  2
• 氢受体数：
  10

反应信息

• 作为产物：
  描述：

  2-(4-((6-chloropyrimidin-4-yl)oxy)phenyl)-N-(4-((4-ethylpiperazin-1-yl)-methyl)-3-(trifluoromethyl)phenyl)acetamide 、 甲胺 以 四氢呋喃 为溶剂， 反应 16.0h， 以49.1 mg的产率得到N-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-2-(4-((6-(methylamino)pyrimidin-4-yl)oxy)phenyl)acetamide
  参考文献：
  名称：

  Structure–Activity Relationship Studies of Mitogen Activated Protein Kinase Interacting Kinase (MNK) 1 and 2 and BCR-ABL1 Inhibitors Targeting Chronic Myeloid Leukemic Cells

  摘要：

  Clinically used BCR-ABL1 inhibitors for the treatment of chronic myeloid leukemia do not eliminate leukemic stem cells (LSC). It has been shown that MNK1 and 2 inhibitors prevent phosphorylation of eIF4E and eliminate the self-renewal capacity of LSCs. Herein, we describe the identification of novel dual MNK1 and 2 and BCR-ABL1 inhibitors, starting from the known kinase inhibitor 2. Initial structure activity relationship studies resulted in compound 27 with loss of BCR-ABL1 inhibition. Further modification led to orally bioavailable dual MNK1 and 2 and BCR-ABL1 inhibitors 53 and 54, which are efficacious in a mouse xenograft model and also reduce the level of phosphorylated eukaryotic translation initiation factor 4E in the tumor tissues. Kinase selectivity of these compounds is also presented.

  DOI：

  10.1021/acs.jmedchem.5b01712

文献信息

• Structure–Activity Relationship Studies of Mitogen Activated Protein Kinase Interacting Kinase (MNK) 1 and 2 and BCR-ABL1 Inhibitors Targeting Chronic Myeloid Leukemic Cells
  作者：Joseph Cherian、Kassoum Nacro、Zhi Ying Poh、Samantha Guo、Duraiswamy A. Jeyaraj、Yun Xuan Wong、Melvyn Ho、Hai Yan Yang、Joma Kanikadu Joy、Zekui Perlyn Kwek、Boping Liu、John Liang Kuan Wee、Esther HQ Ong、Meng Ling Choong、Anders Poulsen、May Ann Lee、Vishal Pendharkar、Li Jun Ding、Vithya Manoharan、Yun Shan Chew、Kanda Sangthongpitag、Sharon Lim、S. Tiong Ong、Jeffrey Hill、Thomas H. Keller

  DOI：10.1021/acs.jmedchem.5b01712

  日期：2016.4.14

  Clinically used BCR-ABL1 inhibitors for the treatment of chronic myeloid leukemia do not eliminate leukemic stem cells (LSC). It has been shown that MNK1 and 2 inhibitors prevent phosphorylation of eIF4E and eliminate the self-renewal capacity of LSCs. Herein, we describe the identification of novel dual MNK1 and 2 and BCR-ABL1 inhibitors, starting from the known kinase inhibitor 2. Initial structure activity relationship studies resulted in compound 27 with loss of BCR-ABL1 inhibition. Further modification led to orally bioavailable dual MNK1 and 2 and BCR-ABL1 inhibitors 53 and 54, which are efficacious in a mouse xenograft model and also reduce the level of phosphorylated eukaryotic translation initiation factor 4E in the tumor tissues. Kinase selectivity of these compounds is also presented.