3-(3-(quinolin-6-ylmethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl)benzonitrile | 1022088-63-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 英文名称: 3-(3-(quinolin-6-ylmethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl)benzonitrile
• 英文别名: 3-[3-(Quinolin-6-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]benzonitrile
• CAS: 1022088-63-6
• 化学式: C₂₂H₁₄N₆
• 分子量: 362.393
• InChiKey: AWPGEMDEIDCXMW-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.3
• 重原子数：
  28
• 可旋转键数：
  3
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.05
• 拓扑面积：
  79.8
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  6-喹啉乙酸 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 作用下， 以 乙二醇二甲醚 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 2.5h， 生成 3-(3-(quinolin-6-ylmethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl)benzonitrile
  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

• TRIAZOLOPYRIDAZINE PROTEIN KINASE MODULATORS
  申请人：Smith Christopher Ronald

  公开号：US20100120739A1

  公开（公告）日：2010-05-13

  The present disclosure relates to triazolopyridazine protein kinase modulators of Formula (I), methods of using these compounds to treat diseases mediated by kinase activity.

  本公开涉及式(I)的三唑并吡嗪蛋白激酶调节剂，以及使用这些化合物治疗由激酶活性介导的疾病的方法。
• US8071581B2
  申请人：——

  公开号：US8071581B2

  公开（公告）日：2011-12-06
• [EN] TRIAZOLOPYRIDAZINE PROTEIN KINASE MODULATORS<br/>[FR] MODULATEURS DE PROTÉINES KINASES À BASE DE TRIAZOLOPYRIDAZINES
  申请人：SGX PHARMACEUTICALS INC

  公开号：WO2008051805A2

  公开（公告）日：2008-05-02

  [EN] The present disclosure relates to tirazalopyridazine protein kinase modulators and methods of using these compounds to treat diseases mediated by kinase activity.
  [FR] La présente invention concerne des modulateurs de protéines kinases à base de triazolopyridazines et des procédés d'utilisation de ces composés pour traiter des maladies médiées par une activité kinase.
• 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.