(4-methylpiperazin-1-yl)(4-(3-p-tolylimidazo[1,2-a]pyrazin-6-yl)phenyl)methanone

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: (4-methylpiperazin-1-yl)(4-(3-p-tolylimidazo[1,2-a]pyrazin-6-yl)phenyl)methanone
• 英文别名: [4-[3-(4-Methylphenyl)imidazo[1,2-a]pyrazin-6-yl]phenyl]-(4-methylpiperazin-1-yl)methanone；[4-[3-(4-methylphenyl)imidazo[1,2-a]pyrazin-6-yl]phenyl]-(4-methylpiperazin-1-yl)methanone
• 化学式: C₂₅H₂₅N₅O
• 分子量: 411.506
• InChiKey: AJSPQFHUVJMVLQ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.7
• 重原子数：
  31
• 可旋转键数：
  3
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.24
• 拓扑面积：
  53.7
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  4-乙氧羰基苯硼酸 在 N-甲基吗啉 、 N-溴代丁二酰亚胺(NBS) 、 四(三苯基膦)钯 、 caesium carbonate 、 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 、 四氯化碳 、 水 、 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 39.5h， 生成 (4-methylpiperazin-1-yl)(4-(3-p-tolylimidazo[1,2-a]pyrazin-6-yl)phenyl)methanone
  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

文献信息

• BICYCLIC HETEROARYL DERIVATIVES AS MNK1 AND MNK2 MODULATORS AND USES THEREOF
  申请人：Agency for Science, Technology and Research

  公开号：US20190211020A1

  公开（公告）日：2019-07-11

  The present invention relates to certain compounds (e.g., imidazopyrazine, imidazopyridine, imidazopyridazine and imidazpyrimidine compounds) that act as inhibitors of the MAP kinase interacting kinases MNK2a, MNK2b, MNK1a, and MNK1b. The present invention further relates to pharmaceutical compositions comprising these compounds, and to the use of the compounds for the preparation of a medicament for the prophylaxis and treatment of diseases (e.g., proliferative diseases (e.g., cancer), neurodegenerative diseases (e.g., Alzheimer's disease), metabolic diseases (e.g. diabetes), neurodevelopmental disorders (e.g. autism), or psychiatric disorders (e.g. schizophrenia or anxiety)) as well as methods of treating these diseases.
• Optimization of Selective Mitogen-Activated Protein Kinase Interacting Kinases 1 and 2 Inhibitors for the Treatment of Blast Crisis Leukemia
  作者：Haiyan Yang、Lohitha Rao Chennamaneni、Melvyn Wai Tuck Ho、Shi Hua Ang、Eldwin Sum Wai Tan、Duraiswamy Athisayamani Jeyaraj、Yoon Sheng Yeap、Boping Liu、Esther Hq Ong、Joma Kanikadu Joy、John Liang Kuan Wee、Perlyn Kwek、Priya Retna、Nurul Dinie、Thuy Thi Hanh Nguyen、Shi Jing Tai、Vithya Manoharan、Vishal Pendharkar、Choon Bing Low、Yun Shan Chew、Susmitha Vuddagiri、Kanda Sangthongpitag、Meng Ling Choong、May Ann Lee、Srinivasaraghavan Kannan、Chandra S. Verma、Anders Poulsen、Sharon Lim、Charles Chuah、Tiong Sin Ong、Jeffrey Hill、Alex Matter、Kassoum Nacro

  DOI：10.1021/acs.jmedchem.7b01714

  日期：2018.5.24

  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.