1-(4-(4-(3-(4-hydroxyphenyl)imidazo[1,2-a]pyrazin-6-yl)benzoyl)piperazin-1-yl)ethanone

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 1-(4-(4-(3-(4-hydroxyphenyl)imidazo[1,2-a]pyrazin-6-yl)benzoyl)piperazin-1-yl)ethanone
• 英文别名: 1-[4-[4-[3-(4-Hydroxyphenyl)imidazo[1,2-a]pyrazin-6-yl]benzoyl]piperazin-1-yl]ethanone；1-[4-[4-[3-(4-hydroxyphenyl)imidazo[1,2-a]pyrazin-6-yl]benzoyl]piperazin-1-yl]ethanone
• 化学式: C₂₅H₂₃N₅O₃
• 分子量: 441.489
• InChiKey: KJZWOUQMPQCYIK-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.4
• 重原子数：
  33
• 可旋转键数：
  3
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.2
• 拓扑面积：
  91
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  3-bromo-6-iodoimidazo[1,2-a]pyrazine 在 N-甲基吗啉 、 四(三苯基膦)钯 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 、 lithium hydroxide 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 甲醇 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 32.0h， 生成 1-(4-(4-(3-(4-hydroxyphenyl)imidazo[1,2-a]pyrazin-6-yl)benzoyl)piperazin-1-yl)ethanone
  参考文献：
  名称：

  Optimization of Selective Mitogen-Activated Protein Kinase Interacting Kinases 1 and 2 Inhibitors for the Treatment of Blast Crisis Leukemia

  摘要：

  Chronic myeloid leukemia (CML) is a myeloproliferative disease caused by bcr-abll, a constitutively active tyrosine kinase fusion gene responsible for an abnormal proliferation of leukemic stem cells (LSCs). Inhibition of BCR-ABL1 kinase activity offers long-term relief to CML patients. However, for a proportion of them, BCR-ABL1 inhibition will become ineffective at treating the disease, and CML will progress to blast crisis (BC) CML with poor prognosis. BC-CML is often associated with excessive phosphorylated eukaryotic translation initiation factor 4E (eIF4E), which renders LSCs capable of proliferating via self-renewal, oblivious to BCR-ABL1 inhibition. In vivo, eIF4E is exclusively phosphorylated on Ser209 by MNK1/2. Consequently, a selective inhibitor of MNK1/2 should reduce the level of phosphorylated eIF4E and re-sensitize LSCs to BCR-ABL1 inhibition, thus hindering the proliferation of BC LSCs. We report herein the structure activity relationships and pharmacokinetic properties of a selective MNK1/2 inhibitor clinical candidate, ETC-206, which in combination with dasatinib prevents BC-CML LSC self-renewal in vitro and enhances dasatinib antitumor activity in vivo.

  DOI：

  10.1021/acs.jmedchem.7b01714