1-[4-[2-amino-3-[3-(dimethylamino)prop-1-ynyl]pyridin-4-yl]oxy-3-fluorophenyl]-N-[(4-fluorophenyl)methyl]-6-oxopyridine-3-carboxamide | 1386374-22-6

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 1-[4-[2-amino-3-[3-(dimethylamino)prop-1-ynyl]pyridin-4-yl]oxy-3-fluorophenyl]-N-[(4-fluorophenyl)methyl]-6-oxopyridine-3-carboxamide
• CAS: 1386374-22-6
• 化学式: C₂₉H₂₅F₂N₅O₃
• 分子量: 529.546
• InChiKey: PRYSLJCRIVHTSF-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3
• 重原子数：
  39
• 可旋转键数：
  8
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.14
• 拓扑面积：
  101
• 氢给体数：
  2
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  在 4-二甲氨基吡啶 、 potassium tert-butylate 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 sodium hydroxide 作用下， 以 甲醇 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 14.0h， 生成 1-[4-[2-amino-3-[3-(dimethylamino)prop-1-ynyl]pyridin-4-yl]oxy-3-fluorophenyl]-N-[(4-fluorophenyl)methyl]-6-oxopyridine-3-carboxamide
  参考文献：
  名称：

  Design, synthesis and evaluation of highly selective pyridone-based class II MET inhibitors

  摘要：

  The high incidence of MET oncogene activation in human malignancies has prompted researchers to develop MET inhibitors. As part of our efforts to developing effective and safe therapeutic agents against MET-dependent tumors, a pyridone-based class II MET inhibitor, namely, 1-(4-((2-amino-3-iodopyridin-4-yl)-oxy)-3-fluorophenyl)-N-(4-fluorobenzyl)-4-methoxy-6-oxo-1,6-dihydropyridine-3-carboxamide (3s), was identified. Knowledge of the binding mode of class II MET inhibitors led to the design of new inhibitors that utilize 2-pyridone to conformationally restrain key pharmacophoric groups within the molecule. Integrated molecular docking and SAR studies resulted in the discovery of a novel class of pyridone MET inhibitors with high potency (IC50 of 0.005 mu M) and efficient selectivity (>5000 fold) to VEGFR-2, c-Kit and RET kinases. (C) 2014 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2014.05.097

文献信息

• Design, synthesis and evaluation of highly selective pyridone-based class II MET inhibitors
  作者：Nengfang She、Linsheng Zhuo、Wen Jiang、Xiaolei Zhu、Jia Wang、Zhihui Ming、Xinge Zhao、Xin Cong、Wei Huang

  DOI：10.1016/j.bmcl.2014.05.097

  日期：2014.8

  The high incidence of MET oncogene activation in human malignancies has prompted researchers to develop MET inhibitors. As part of our efforts to developing effective and safe therapeutic agents against MET-dependent tumors, a pyridone-based class II MET inhibitor, namely, 1-(4-((2-amino-3-iodopyridin-4-yl)-oxy)-3-fluorophenyl)-N-(4-fluorobenzyl)-4-methoxy-6-oxo-1,6-dihydropyridine-3-carboxamide (3s), was identified. Knowledge of the binding mode of class II MET inhibitors led to the design of new inhibitors that utilize 2-pyridone to conformationally restrain key pharmacophoric groups within the molecule. Integrated molecular docking and SAR studies resulted in the discovery of a novel class of pyridone MET inhibitors with high potency (IC50 of 0.005 mu M) and efficient selectivity (>5000 fold) to VEGFR-2, c-Kit and RET kinases. (C) 2014 Elsevier Ltd. All rights reserved.