2-((2-aminoethyl)amino)-5,7-dimethylquinoline-3-carbonitrile | 604754-35-0

• 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: 2-((2-aminoethyl)amino)-5,7-dimethylquinoline-3-carbonitrile
• 英文别名: 2-(2-aminoethylamino)-5,7-dimethylquinoline-3-carbonitrile
• CAS: 604754-35-0
• 化学式: C₁₄H₁₆N₄
• 分子量: 240.308
• InChiKey: UMAWAEYVRVSDFI-UHFFFAOYSA-N

物化性质

• 沸点：
  478.4±45.0 °C(Predicted)
• 密度：
  1.18±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.6
• 重原子数：
  18
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  74.7
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  2-((2-aminoethyl)amino)-5,7-dimethylquinoline-3-carbonitrile 、 藜芦酸 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41%的产率得到N-(2-((3-cyano-5,7-dimethylquinolin-2-yl)amino)ethyl)-3,4-dimethoxybenzamide
  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 盐酸羟胺 、 三乙胺 作用下， 以 1,4-二氧六环 、 乙醇 为溶剂， 反应 7.0h， 生成 2-((2-aminoethyl)amino)-5,7-dimethylquinoline-3-carbonitrile
  参考文献：
  名称：

  Cyanoquinolines with Independent Corrector and Potentiator Activities Restore ΔPhe508-Cystic Fibrosis Transmembrane Conductance Regulator Chloride Channel Function in Cystic Fibrosis

  摘要：

  囊性纤维化跨膜传导调节器（CFTR）蛋白中的ΔPhe508突变会损害其折叠、稳定性和氯离子通道门控。尽管已经发现了可分别纠正ΔPhe508-CFTR折叠/细胞处理缺陷（"纠正剂"）或氯离子通道门控缺陷（"增效剂"）的小分子化合物，并已进入临床试验阶段，但具有真正双重纠正剂和增效剂活性的单一化合物尚未发现。在这里，通过筛选以前未测试过的∼110,000 个小分子，发现了一类具有独立校正器和增效剂活性的氰基喹啉类化合物（称为 CoPo）。对 180 种 CoPo 类似物的分析表明，6 种化合物具有校正和增效双重活性，13 种化合物仅具有增效活性。N -(2-((3-氰基-5,7-二甲基喹啉-2-基)氨基)乙基)-3-甲氧基苯甲酰胺（CoPo-22）分六步合成，总收率为 52%，通过短路电流测定，该化合物对 ΔPhe508-CFTR 校正器和增效剂活性的 EC50 值较低。最大校正器和增效剂活性分别与双噻唑 Corr-4a 和黄酮染料木素所赋予的活性相当。CoPo-22 还能以福斯可林依赖性方式在几分钟内激活野生型和 G551D CFTR 的氯传导。具有纠正剂和增效剂双重活性的化合物可能有助于单药治疗由ΔPhe508突变引起的囊性纤维化。

  DOI：

  10.1124/mol.111.073056

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。
• 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：US09073863B2

  公开（公告）日：2015-07-07

  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、制药制剂和方法，用于增加突变囊性纤维化跨膜传导调节因子蛋白（突变-CFTR）的活性。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，具有用途。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氰喹啉类化合物，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.