N-phenyl-2-(pyridin-4-yl)quinoline-4-carboxamide | 879921-41-2

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: N-phenyl-2-(pyridin-4-yl)quinoline-4-carboxamide
• 英文别名: N-phenyl-2-pyridin-4-ylquinoline-4-carboxamide
• CAS: 879921-41-2
• 化学式: C₂₁H₁₅N₃O
• 分子量: 325.37
• InChiKey: HNHSNBXXGBXNBF-UHFFFAOYSA-N

物化性质

• 熔点：
  202-203 °C
• 沸点：
  477.6±40.0 °C(Predicted)
• 密度：
  1.280±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.6
• 重原子数：
  25
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  54.9
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为产物：
  描述：

  2-(4-吡啶基)-4-喹啉羧酸 在 氯化亚砜 、 三乙胺 作用下， 以 二氯甲烷 为溶剂， 反应 4.0h， 生成 N-phenyl-2-(pyridin-4-yl)quinoline-4-carboxamide
  参考文献：
  名称：

  Small Molecule Quantification by Liquid Chromatography-Mass Spectrometry for Metabolites of Drugs and Drug Candidates

  摘要：

  药物及药物候选物代谢物的鉴定和定量通常使用液相色谱-质谱联用技术 (LC-MS) 进行。最佳实践是生成以代谢物与内标的标准曲线。然而，为了避免代谢物合成的困难，有时会使用底物来准备标准曲线，假设底物和代谢物的信号是等效的。我们使用一系列非常相似的化合物，这些化合物经历共同的代谢反应，测试了这一假设所带来的误差，采用了传统流动电喷雾电离 LC-MS 和低流量捕获喷雾电离 (CSI) LC-MS 方法。文中展示了四种不同转化类型（O-去甲基化、N-去甲基化、芳香族羟基化和苄基羟基化）的标准曲线差异。结果表明，在20种底物-代谢物组合中的18种情况下，两种方法中底物和代谢物的信号在统计上是显著不同的。标准曲线的斜率比率最高可变化4倍，但CSI方法的变化略小。

  DOI：

  10.1124/dmd.111.040865

文献信息

• Small Molecule Quantification by Liquid Chromatography-Mass Spectrometry for Metabolites of Drugs and Drug Candidates
  作者：Upendra P. Dahal、Jeffrey P. Jones、John A. Davis、Dan A. Rock

  DOI：10.1124/dmd.111.040865

  日期：2011.12

  Identification and quantification of the metabolites of drugs and drug candidates are routinely performed using liquid chromatography-mass spectrometry (LC-MS). The best practice is to generate a standard curve with the metabolite versus the internal standard. However, to avoid the difficulties in metabolite synthesis, standard curves are sometimes prepared using the substrate, assuming that the signal for substrate and the metabolite will be equivalent. We have tested the errors associated with this assumption using a series of very similar compounds that undergo common metabolic reactions using both conventional flow electrospray ionization LC-MS and low-flow captive spray ionization (CSI) LC-MS. The differences in standard curves for four different types of transformations (O-demethylation, N-demethylation, aromatic hydroxylation, and benzylic hydroxylation) are presented. The results demonstrate that the signals of the substrates compared with those of the metabolites are statistically different in 18 of the 20 substrate-metabolite combinations for both methods. The ratio of the slopes of the standard curves varied up to 4-fold but was slightly less for the CSI method.

  药物及药物候选物代谢物的鉴定和定量通常使用液相色谱-质谱联用技术 (LC-MS) 进行。最佳实践是生成以代谢物与内标的标准曲线。然而，为了避免代谢物合成的困难，有时会使用底物来准备标准曲线，假设底物和代谢物的信号是等效的。我们使用一系列非常相似的化合物，这些化合物经历共同的代谢反应，测试了这一假设所带来的误差，采用了传统流动电喷雾电离 LC-MS 和低流量捕获喷雾电离 (CSI) LC-MS 方法。文中展示了四种不同转化类型（O-去甲基化、N-去甲基化、芳香族羟基化和苄基羟基化）的标准曲线差异。结果表明，在20种底物-代谢物组合中的18种情况下，两种方法中底物和代谢物的信号在统计上是显著不同的。标准曲线的斜率比率最高可变化4倍，但CSI方法的变化略小。
• Cytochrome P450 2C9 Type II Binding Studies on Quinoline-4-Carboxamide Analogues
  作者：Chi-Chi Peng、Jonathan L. Cape、Tom Rushmore、Gregory J. Crouch、Jeffrey P. Jones

  DOI：10.1021/jm8011257

  日期：2008.12.25

  CYP2C9 is a significant P450 protein responsible for drug metabolism. With the increased use of heterocyclic compounds in drug design, a rapid and efficient predrug screening of these potential type II binding compounds is essential to avoid adverse drug reactions. To understand binding modes, we use quinoline-4-carboxamide analogues to study the factors that determine the structure-activity relationships. The results of this study suggest that the more accessible pyridine with the nitrogen para to the linkage can coordinate directly with the ferric heme iron, but this is not seen for the meta or ortho isomers. The pi-cation interaction of the naphthalene moiety and Arg 108 residue may also assist in stabilizing Substrate binding within the active-site cavity. The type II substrate binding affinity is determined by the combination of steric, electrostatic, and hydrophobicity factors; meanwhile, it is enhanced by the strength of lone pair electrons coordination with the heme iron.
• Comparative Study of the Affinity and Metabolism of Type I and Type II Binding Quinoline Carboxamide Analogues by Cytochrome P450 3A4
  作者：Upendra P. Dahal、Carolyn Joswig-Jones、Jeffrey P. Jones

  DOI：10.1021/jm201207h

  日期：2012.1.12

  Compounds that coordinate to the heme-iron of cytochrome P450 (CYP) enzymes are assumed to increase metabolic stability. However, recently we observed that the type II binding quinoline carboxamide (QCA) compounds were metabolically less stable. To test if the higher intrinsic clearance of type II binding compounds relative to type I binding compounds is general for other metabolic transformations, we synthesized a library of QCA compounds that could undergo N-dealkylation, O-dealkylation, benzylic hydroxylation, and aromatic hydroxylation. The results demonstrated that type II binding QCA analogues were metabolically less stable (2- to 12-fold) at subsaturating concentration compared to type I binding counterparts for all the transformations. When the rates of different metabolic transformations between type I and type II binding compounds were compared, they were found to be in the order of N-demethylation > benzylic hydroxylation > O-demethylation > aromatic hydroxylation. Finally, for the QCA analogues with aza-heteroaromatic rings, we did not detect metabolism in aza-aromatic rings (pyridine, pyrazine, pyrimidine), indicating that electronegativity of the nitrogen can change regioselectivity in CYP metabolism.