5,7-二甲基-2-(哌嗪-1-基)喹啉-3-甲腈 | 1018617-87-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪烷类
• 中文名称: 5,7-二甲基-2-(哌嗪-1-基)喹啉-3-甲腈
• 英文名称: 5,7-dimethyl-2-(piperazin-1-yl)quinoline-3-carbonitrile
• 英文别名: 5,7-Dimethyl-2-piperazino-quinoline-3-carbonitrile；5,7-dimethyl-2-piperazin-1-ylquinoline-3-carbonitrile
• CAS: 1018617-87-2
• 化学式: C₁₆H₁₈N₄
• 分子量: 266.346
• InChiKey: AGWQWXZPAVLKSU-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.4
• 重原子数：
  20
• 可旋转键数：
  1
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  52
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  5,7-二甲基-2-(哌嗪-1-基)喹啉-3-甲腈 、 3-甲氧基苯甲酸 在 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 作用下， 以 二氯甲烷 为溶剂， 反应 18.5h， 以50%的产率得到2-(4-(3-methoxybenzoyl)piperazin-1-yl)-5,7-dimethylquinoline-3-carbonitrile
  参考文献：
  名称：

  Structure–Activity Relationships of Cyanoquinolines with Corrector–Potentiator Activity in ΔF508 Cystic Fibrosis Transmembrane Conductance Regulator Protein

  摘要：

  Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel. The most common CF-causing mutation, Delta F508-CFTR, produces CFTR loss-of-function by impairing its cellular targeting to the plasma membrane and its chloride channel gating. We recently identified cyanoquinolines with both corrector ("Co", normalizing Delta F508-CFTR targeting) and potentiator ("Po", normalizing Delta F508-CFTR channel gating) activities. Here, we synthesized and characterized 24 targeted cyanoquinoline analogues to elucidate the conformational requirements for corrector and potentiator activities. Compounds with potentiator-only, corrector-only, and dual potentiator-corrector activities were found. Molecular modeling studies (conformational search double right arrow force-field lowest energy assessment double right arrow geometry optimization) suggest that (1) a flexible tether and (2) a relatively short bridge between the cyanoquinoline and arylamide moieties are important cyanoquinoline-based CoPo features. Further, these CoPo's may adopt two distinct pi-stacking conformations to elicit corrector and potentiator activities.

  DOI：

  10.1021/jm201372q
• 作为产物：
  描述：

  2-氯-5,7-二甲基-3-喹啉甲醛 在 氯化亚砜 、 盐酸羟胺 、 三乙胺 作用下， 以 1,4-二氧六环 、 乙醇 、 苯 为溶剂， 反应 7.0h， 生成 5,7-二甲基-2-(哌嗪-1-基)喹啉-3-甲腈
  参考文献：
  名称：

  Structure–Activity Relationships of Cyanoquinolines with Corrector–Potentiator Activity in ΔF508 Cystic Fibrosis Transmembrane Conductance Regulator Protein

  摘要：

  Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel. The most common CF-causing mutation, Delta F508-CFTR, produces CFTR loss-of-function by impairing its cellular targeting to the plasma membrane and its chloride channel gating. We recently identified cyanoquinolines with both corrector ("Co", normalizing Delta F508-CFTR targeting) and potentiator ("Po", normalizing Delta F508-CFTR channel gating) activities. Here, we synthesized and characterized 24 targeted cyanoquinoline analogues to elucidate the conformational requirements for corrector and potentiator activities. Compounds with potentiator-only, corrector-only, and dual potentiator-corrector activities were found. Molecular modeling studies (conformational search double right arrow force-field lowest energy assessment double right arrow geometry optimization) suggest that (1) a flexible tether and (2) a relatively short bridge between the cyanoquinoline and arylamide moieties are important cyanoquinoline-based CoPo features. Further, these CoPo's may adopt two distinct pi-stacking conformations to elicit corrector and potentiator activities.

  DOI：

  10.1021/jm201372q

文献信息

• [EN] CYANOQUINOLINE COMPOUNDS HAVING ACTIVITY IN CORRECTING MUTANT-CFTR PROCESSING AND INCREASING ION TRANSPORT AND USES THEREOF<br/>[FR] COMPOSÉS DE CYANOQUINOLÉINE AYANT UNE ACTIVITÉ POUR CORRIGER LE TRAITEMENT DE LA PROTÉINE CFTR MUTANTE ET AUGMENTER LE TRANSPORT IONIQUE ET LES UTILISATIONS DE CEUX-CI
  申请人：UNIV CALIFORNIA

  公开号：WO2012166654A1

  公开（公告）日：2012-12-06

  The present disclosure provides pharmaceutical compositions, pharmaceutical preparations and methods for increasing activity of a mutant cystic fibrosis transmembrane conductance regulator protein (mutant-CFTR). The pharmaceutical compositions, pharmaceutical preparations and methods are useful for the study and treatment of disorders associated with mutant-CFTR, such as cystic fibrosis. The pharmaceutical compositions and pharmaceutical preparations may include one or more cyanoquinoline-containing compounds of the embodiments, or an analog or derivative thereof.

  本公开提供了制药组合物、制药制剂和增加突变型囊性纤维化跨膜传导调节因子蛋白（突变-CFTR）活性的方法。这些制药组合物、制药制剂和方法对于研究和治疗与突变-CFTR相关的疾病，如囊性纤维化病非常有用。这些制药组合物和制药制剂可能包括本实施例中的一个或多个含有氰基喹啉的化合物，或其类似物或衍生物。
• Cyanoquinoline Compounds Having Activity in Correcting Mutant-Cftr Processing and Increasing Ion Transport and Uses Thereof
  申请人：Verkman Alan S.

  公开号：US20140296215A1

  公开（公告）日：2014-10-02

  The present disclosure provides pharmaceutical compositions, pharmaceutical preparations and methods for increasing activity of a mutant cystic fibrosis transmembrane conductance regulator protein (mutant-CFTR). The pharmaceutical compositions, pharmaceutical preparations and methods are useful for the study and treatment of disorders associated with mutant-CFTR, such as cystic fibrosis. The pharmaceutical compositions and pharmaceutical preparations may include one or more cyanoquinoline-containing compounds of the embodiments, or an analog or derivative thereof.

  本公开提供了药物组成物、药物制剂和方法，用于增加突变型囊性纤维化跨膜传导调节因子蛋白（突变-CFTR）的活性。这些药物组成物、药物制剂和方法对于研究和治疗与突变-CFTR相关的疾病，如囊性纤维化，具有用处。药物组成物和药物制剂可以包括本实施例中的一种或多种含有氰基喹啉的化合物，或其类似物或衍生物。
• US9073863B2
  申请人：——

  公开号：US9073863B2

  公开（公告）日：2015-07-07
• Structure–Activity Relationships of Cyanoquinolines with Corrector–Potentiator Activity in ΔF508 Cystic Fibrosis Transmembrane Conductance Regulator Protein
  作者：John M. Knapp、Alex B. Wood、Puay-Wah Phuan、Michael W. Lodewyk、Dean J. Tantillo、A. S. Verkman、Mark J. Kurth

  DOI：10.1021/jm201372q

  日期：2012.2.9

  Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel. The most common CF-causing mutation, Delta F508-CFTR, produces CFTR loss-of-function by impairing its cellular targeting to the plasma membrane and its chloride channel gating. We recently identified cyanoquinolines with both corrector ("Co", normalizing Delta F508-CFTR targeting) and potentiator ("Po", normalizing Delta F508-CFTR channel gating) activities. Here, we synthesized and characterized 24 targeted cyanoquinoline analogues to elucidate the conformational requirements for corrector and potentiator activities. Compounds with potentiator-only, corrector-only, and dual potentiator-corrector activities were found. Molecular modeling studies (conformational search double right arrow force-field lowest energy assessment double right arrow geometry optimization) suggest that (1) a flexible tether and (2) a relatively short bridge between the cyanoquinoline and arylamide moieties are important cyanoquinoline-based CoPo features. Further, these CoPo's may adopt two distinct pi-stacking conformations to elicit corrector and potentiator activities.