1-Amino-5-(5-Hydroxy-2-Methylphenyl)-7,8,9,10-Tetrahydropyrimido[4,5-C]isoquinolin-6(5h)-One | 1394837-94-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 异喹啉及其衍生物
• 英文名称: 1-Amino-5-(5-Hydroxy-2-Methylphenyl)-7,8,9,10-Tetrahydropyrimido[4,5-C]isoquinolin-6(5h)-One
• 英文别名: 1-amino-5-(5-hydroxy-2-methylphenyl)-7,8,9,10-tetrahydropyrimido[4,5-c]isoquinolin-6-one
• CAS: 1394837-94-5
• 化学式: C₁₈H₁₈N₄O₂
• 分子量: 322.367
• InChiKey: ZQQZSFIPDUAFMC-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.3
• 重原子数：
  24
• 可旋转键数：
  1
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.28
• 拓扑面积：
  92.3
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  2,2-dimethyl-5,6,7,8-tetrahydro-4H-benzo[d][1,3]dioxin-4-one 在 哌啶 、 三溴化硼 作用下， 以 乙醇 、 二氯甲烷 、 邻二甲苯 为溶剂， 反应 25.08h， 生成 1-Amino-5-(5-Hydroxy-2-Methylphenyl)-7,8,9,10-Tetrahydropyrimido[4,5-C]isoquinolin-6(5h)-One
  参考文献：
  名称：

  Discovery of a Novel Chemotype of Tyrosine Kinase Inhibitors by Fragment-Based Docking and Molecular Dynamics

  摘要：

  We have discovered a novel chemical class of inhibitors of the EphB4 tyrosine kinase by fragment-based high-throughput docking followed by explicit solvent molecular dynamics simulations for assessment of the binding mode. The synthesis of a single derivative (compound 7) of the hit identified in silico has resulted in an improvement of the inhibitory potency in an enzymatic assay from 8.4 mu M to 160 nM and a ligand efficiency of 0.39 kcal/mol per non-hydrogen atom. Such remarkable improvement in affinity is due to an additional hydroxyl group involved in two favorable (buried) hydrogen bonds as predicted by molecular dynamics and validated by the crystal structure of the complex with EphA3 solved at 1.7 angstrom resolution.

  DOI：

  10.1021/ml3001984

文献信息

• Discovery of a Novel Chemotype of Tyrosine Kinase Inhibitors by Fragment-Based Docking and Molecular Dynamics
  作者：Hongtao Zhao、Jing Dong、Karine Lafleur、Cristina Nevado、Amedeo Caflisch

  DOI：10.1021/ml3001984

  日期：2012.10.11

  We have discovered a novel chemical class of inhibitors of the EphB4 tyrosine kinase by fragment-based high-throughput docking followed by explicit solvent molecular dynamics simulations for assessment of the binding mode. The synthesis of a single derivative (compound 7) of the hit identified in silico has resulted in an improvement of the inhibitory potency in an enzymatic assay from 8.4 mu M to 160 nM and a ligand efficiency of 0.39 kcal/mol per non-hydrogen atom. Such remarkable improvement in affinity is due to an additional hydroxyl group involved in two favorable (buried) hydrogen bonds as predicted by molecular dynamics and validated by the crystal structure of the complex with EphA3 solved at 1.7 angstrom resolution.