4-dimethylaminobutanoic acid [4-(5-chloro-4-fluoro-3-methylphenylamino)-3-methyl-7-methoxyquinolin-6-yl]amide hydrochloride | 1050672-70-2

• 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: 4-dimethylaminobutanoic acid [4-(5-chloro-4-fluoro-3-methylphenylamino)-3-methyl-7-methoxyquinolin-6-yl]amide hydrochloride
• CAS: 1050672-70-2
• 化学式: C₂₄H₂₈ClFN₄O₂*ClH
• 分子量: 495.424
• InChiKey: PRXRSHFPUAFJCN-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.1
• 重原子数：
  33.0
• 可旋转键数：
  8.0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  66.49
• 氢给体数：
  2.0
• 氢受体数：
  5.0

反应信息

• 作为产物：
  描述：

  4-(3-methyl-4-fluoro-5-chlorophenylamino)-7-methoxy-6-aminoquinoline-3-methyl hydrochloride 、 4-(dimethylamino)butanoyl chloride 在 N,N-二异丙基乙胺 作用下， 以 四氢呋喃 为溶剂， 以13.5 g的产率得到4-dimethylaminobutanoic acid [4-(5-chloro-4-fluoro-3-methylphenylamino)-3-methyl-7-methoxyquinolin-6-yl]amide hydrochloride
  参考文献：
  名称：

  Redesigning Kinase Inhibitors to Enhance Specificity

  摘要：

  Kinases are important targets in molecular cancer therapy. However, the evolutionary relatedness and structural conservation of these proteins often lead to unforeseen cross reactivity, yielding unexpected side effects. Thus, the use of promiscuous drugs is likely to introduce dangerous clinical uncertainties. Here, we show how to rationally redesign two promiscuous kinase inhibitors, staurosporine (7) and EKB-569 (8), with the goal of turning, them into more selective ligands. This problem is addressed by exploiting a structure-based selectivity filter for specificity: the pattern of packing defects in the target. These singularities, called dehydrons, are solvent-exposed intramolecular hydrogen bonds that may be protected by drugs upon association and are not conserved across protein families. Our redesigned compounds possess a significantly focused activity, as experimentally corroborated in high-throughput screening assays. Thus, our design strategy proves to be operative to reduce the inhibitory impact of promiscuous kinase ligands, enhancing their safety as therapeutic agents.

  DOI：

  10.1021/jm800453a