(S)-3-(1-(1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl)-N-ethyl[1,2,4]triazolo[4,3-b]pyridazin-6-amine | 1452839-92-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 三唑并哒嗪类
• 英文名称: (S)-3-(1-(1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl)-N-ethyl[1,2,4]triazolo[4,3-b]pyridazin-6-amine
• 英文别名: N-ethyl-3-[(1S)-1-(1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl]-[1,2,4]triazolo[4,3-b]pyridazin-6-amine
• CAS: 1452839-92-7
• 化学式: C₁₆H₁₇N₇
• 分子量: 307.358
• InChiKey: BATGVEFXCKJLAL-JTQLQIEISA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.1
• 重原子数：
  23
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.25
• 拓扑面积：
  83.8
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  2-(1H-pyrrolo[2,3-b]pyridin-3-yl)propanoic acid 在 氯化亚砜 作用下， 以 甲醇 、 正丁醇 为溶剂， 反应 2.5h， 生成 (S)-3-(1-(1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl)-N-ethyl[1,2,4]triazolo[4,3-b]pyridazin-6-amine
  参考文献：
  名称：

  Lessons from (S)-6-(1-(6-(1-Methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)ethyl)quinoline (PF-04254644), an Inhibitor of Receptor Tyrosine Kinase c-Met with High Protein Kinase Selectivity but Broad Phosphodiesterase Family Inhibition Leading to Myocardial Degeneration in Rats

  摘要：

  The hepatocyte growth factor (HGF)/c-Met signaling axis is deregulated in many cancers and plays important roles in tumor invasive growth and metastasis. An exclusively selective c-Met inhibitor (S)-6-(1-(6-(1-methyl-1H-pyrazol -4-yl) - [1,2,4] triazolo [4,3-b pyridazin- 3-yl) ethyl) quinoline (8) was discovered from a highly selective high-throughput screening hit. via structure-based drug design and medicinal chemistry lead optimization. Compound 8 had many attractive properties meriting preclinical evaluation. Broad off-target screens identified 8 as a pan-phosphodiesterase (PDE) family inhibitor, which was implicated in a sustained increase in heart rate, increased cardiac output, and decreased contractility indices, as well as myocardial degeneration in in vivo safety evaluations in rats. Compound 8 was terminated as a preclinical candidate because of a narrow therapeutic window in cardio-related safety. The learning from multiparameter lead optimization and strategies to avoid the toxicity attrition at the late stage of drug discovery are discussed.

  DOI：

  10.1021/jm400926x

文献信息

• Lessons from (<i>S</i>)-6-(1-(6-(1-Methyl-1<i>H</i>-pyrazol-4-yl)-[1,2,4]triazolo[4,3-<i>b</i>]pyridazin-3-yl)ethyl)quinoline (PF-04254644), an Inhibitor of Receptor Tyrosine Kinase c-Met with High Protein Kinase Selectivity but Broad Phosphodiesterase Family Inhibition Leading to Myocardial Degeneration in Rats
  作者：J. Jean Cui、Hong Shen、Michelle Tran-Dubé、Mitchell Nambu、Michele McTigue、Neil Grodsky、Kevin Ryan、Shinji Yamazaki、Shirley Aguirre、Max Parker、Qiuhua Li、Helen Zou、James Christensen

  DOI：10.1021/jm400926x

  日期：2013.9.12

  The hepatocyte growth factor (HGF)/c-Met signaling axis is deregulated in many cancers and plays important roles in tumor invasive growth and metastasis. An exclusively selective c-Met inhibitor (S)-6-(1-(6-(1-methyl-1H-pyrazol -4-yl) - [1,2,4] triazolo [4,3-b pyridazin- 3-yl) ethyl) quinoline (8) was discovered from a highly selective high-throughput screening hit. via structure-based drug design and medicinal chemistry lead optimization. Compound 8 had many attractive properties meriting preclinical evaluation. Broad off-target screens identified 8 as a pan-phosphodiesterase (PDE) family inhibitor, which was implicated in a sustained increase in heart rate, increased cardiac output, and decreased contractility indices, as well as myocardial degeneration in in vivo safety evaluations in rats. Compound 8 was terminated as a preclinical candidate because of a narrow therapeutic window in cardio-related safety. The learning from multiparameter lead optimization and strategies to avoid the toxicity attrition at the late stage of drug discovery are discussed.