(S)-6-(1-(6-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)[1,2,4]triazolo[4,3-b]pyridazin-3-yl)ethyl)quinoline | 1452839-87-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 喹啉及其衍生物
• 英文名称: (S)-6-(1-(6-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)[1,2,4]triazolo[4,3-b]pyridazin-3-yl)ethyl)quinoline
• 英文别名: 6-[(1S)-1-[6-(2,3-dihydro-1,4-benzodioxin-6-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl]ethyl]quinoline
• CAS: 1452839-87-0
• 化学式: C₂₄H₁₉N₅O₂
• 分子量: 409.447
• InChiKey: FSMJOBXAIHKUIL-HNNXBMFYSA-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：
  6.0
• sp3杂化的碳原子比例：
  0.17
• 拓扑面积：
  74.4
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  喹啉-6-乙酸甲酯 在 1,1'-双(二苯膦基)二茂铁二氯化钯(II)二氯甲烷复合物 、 caesium carbonate 、 溶剂黄146 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 lithium hydroxide 、 lithium diisopropyl amide 作用下， 以 四氢呋喃 、 甲醇 、 乙二醇二甲醚 、 水 、 N,N-二甲基甲酰胺 为溶剂， -78.0~80.0 ℃ 、10.0 MPa 条件下， 反应 7.0h， 生成 (S)-6-(1-(6-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)[1,2,4]triazolo[4,3-b]pyridazin-3-yl)ethyl)quinoline
  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.