7-(benzyloxy)-4-(6-fluoro-5-methylpyridin-3-yl)-6-methoxycinnoline | 1378294-21-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二氮杂萘
• 英文名称: 7-(benzyloxy)-4-(6-fluoro-5-methylpyridin-3-yl)-6-methoxycinnoline
• 英文别名: 4-(6-Fluoro-5-methylpyridin-3-yl)-6-methoxy-7-phenylmethoxycinnoline
• CAS: 1378294-21-3
• 化学式: C₂₂H₁₈FN₃O₂
• 分子量: 375.402
• InChiKey: ZIKBFTLLRYXKJB-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4
• 重原子数：
  28
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.14
• 拓扑面积：
  57.1
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  7-(benzyloxy)-4-(6-fluoro-5-methylpyridin-3-yl)-6-methoxycinnoline 在 palladium on activated charcoal 、 氢气 作用下， 以 乙醇 为溶剂， 生成 4-(6-fluoro-5-methylpyridin-3-yl)-6-methoxycinnolin-7-ol
  参考文献：
  名称：

  快速鉴定新型小分子磷酸二酯酶10A（PDE10A）示踪剂

  摘要：

  放射性标记的示踪剂，用于在大脑中成像治疗靶标，是在中枢神经系统药物发现中进行铅优化和在临床开发中选择剂量的重要工具。我们报告了使用LC-MS / MS技术对新型磷酸二酯酶10A（PDE10A）示踪剂候选物的快速鉴定。这种结构独特的PDE10A示踪剂AMG-7980（5）已显示在纹状体中具有良好的摄取（1.2％ID / g组织），高特异性（纹状体/丘脑比例为10）和体内可饱和结合。使用[ 3 H] 5确定PDE10A亲和力（K D）和PDE10A目标密度（B max）分别为0.94 nM和2.3 pmol / mg蛋白。对大鼠纹状体匀浆。大鼠脑切片的放射自显影表明示踪信号与已知的PDE10A表达模式一致。[ 3 H] 5与大鼠脑的特异性结合被另一种在结构上不同的已发表的PDE10A抑制剂MP-10阻断。最后，使用LC-MS / MS技术，我们的示踪剂用于测量大鼠中PDE10A抑制剂在体内的PDE10A靶标占有率。

  DOI：

  10.1021/jm3002372
• 作为产物：
  描述：

  4-苄氧基-3-甲氧基苯乙酮 在 四(三苯基膦)钯 、 五氯化磷 、 硫酸 、 硝酸 、 甲酸铵 、 四氯化锡 、 铁粉 、 caesium carbonate 、 sodium nitrite 、 三氯氧磷 作用下， 以 乙二醇二甲醚 、 二氯甲烷 、 水 、 溶剂黄146 、 甲苯 为溶剂， 反应 6.67h， 生成 7-(benzyloxy)-4-(6-fluoro-5-methylpyridin-3-yl)-6-methoxycinnoline
  参考文献：
  名称：

  Synthesis and in vitro characterization of cinnoline and benzimidazole analogues as phosphodiesterase 10A inhibitors

  摘要：

  Fifteen cinnoline analogues and six benzimidazole phosphodiesterase 10A (PDE10A) inhibitors were synthesized as potential PET radiopharmaceuticals and their in vitro activity as PDE10A inhibitors was determined. Nine out of twenty-one compounds were potent inhibitors of PDE10A with IC50 values ranging from 1.5 to 18.6 nM. Notably, the IC50 values of compounds 26a, 26b, and 33c were 1.52 +/- 0.18, 2.86 +/- 0.10, and 3.73 +/- 0.60 nM, respectively; these three compounds also showed high in vitro selectivity (> 1000-fold) for PDE10A over PDE 3A/3B, PDE4A/4B. The high potency and selectivity of these three compounds suggests that they could be radiolabeled with PET radionuclides for further evaluation of their in vivo pharmacological behavior and ability to quantify PDE10A in the brain. (C) 2014 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2014.12.054

文献信息

• Synthesis and in vitro characterization of cinnoline and benzimidazole analogues as phosphodiesterase 10A inhibitors
  作者：Hao Yang、Francis N. Murigi、Zhijian Wang、Junfeng Li、Hongjun Jin、Zhude Tu

  DOI：10.1016/j.bmcl.2014.12.054

  日期：2015.2

  Fifteen cinnoline analogues and six benzimidazole phosphodiesterase 10A (PDE10A) inhibitors were synthesized as potential PET radiopharmaceuticals and their in vitro activity as PDE10A inhibitors was determined. Nine out of twenty-one compounds were potent inhibitors of PDE10A with IC50 values ranging from 1.5 to 18.6 nM. Notably, the IC50 values of compounds 26a, 26b, and 33c were 1.52 +/- 0.18, 2.86 +/- 0.10, and 3.73 +/- 0.60 nM, respectively; these three compounds also showed high in vitro selectivity (> 1000-fold) for PDE10A over PDE 3A/3B, PDE4A/4B. The high potency and selectivity of these three compounds suggests that they could be radiolabeled with PET radionuclides for further evaluation of their in vivo pharmacological behavior and ability to quantify PDE10A in the brain. (C) 2014 Elsevier Ltd. All rights reserved.
• Rapid Identification of a Novel Small Molecule Phosphodiesterase 10A (PDE10A) Tracer
  作者：Essa Hu、Ji Ma、Christopher Biorn、Dianna Lester-Zeiner、Robert Cho、Shannon Rumfelt、Roxanne K. Kunz、Thomas Nixey、Klaus Michelsen、Silke Miller、Jianxia Shi、Jamie Wong、Geraldine Hill Della Puppa、Jessica Able、Santosh Talreja、Dah-Ren Hwang、Stephen A. Hitchcock、Amy Porter、David Immke、Jennifer R. Allen、James Treanor、Hang Chen

  DOI：10.1021/jm3002372

  日期：2012.5.24

  report the rapid identification of a novel phosphodiesterase 10A (PDE10A) tracer candidate using a LC–MS/MS technology. This structurally distinct PDE10A tracer, AMG-7980 (5), has been shown to have good uptake in the striatum (1.2% ID/g tissue), high specificity (striatum/thalamus ratio of 10), and saturable binding in vivo. The PDE10A affinity (KD) and PDE10A target density (Bmax) were determined to

  放射性标记的示踪剂，用于在大脑中成像治疗靶标，是在中枢神经系统药物发现中进行铅优化和在临床开发中选择剂量的重要工具。我们报告了使用LC-MS / MS技术对新型磷酸二酯酶10A（PDE10A）示踪剂候选物的快速鉴定。这种结构独特的PDE10A示踪剂AMG-7980（5）已显示在纹状体中具有良好的摄取（1.2％ID / g组织），高特异性（纹状体/丘脑比例为10）和体内可饱和结合。使用[ 3 H] 5确定PDE10A亲和力（K D）和PDE10A目标密度（B max）分别为0.94 nM和2.3 pmol / mg蛋白。对大鼠纹状体匀浆。大鼠脑切片的放射自显影表明示踪信号与已知的PDE10A表达模式一致。[ 3 H] 5与大鼠脑的特异性结合被另一种在结构上不同的已发表的PDE10A抑制剂MP-10阻断。最后，使用LC-MS / MS技术，我们的示踪剂用于测量大鼠中PDE10A抑制剂在体内的PDE10A靶标占有率。