RL62 | 1160934-75-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: RL62
• 英文别名: 1-(3-(6-aminoquinazolin-4-ylamino)phenyl)-3-(3-tert-butyl-1-m-tolyl-1H-pyrazol-5-yl)urea；1-{3-[(6-aminoquinazolin-4-yl)amino]phenyl}-3-[3-tert-butyl-1-(3-methylphenyl)-1H-pyrazol-5-yl]urea；1-[3-[(6-aminoquinazolin-4-yl)amino]phenyl]-3-[5-tert-butyl-2-(3-methylphenyl)pyrazol-3-yl]urea
• CAS: 1160934-75-7
• 化学式: C₂₉H₃₀N₈O
• 分子量: 506.61
• InChiKey: MWDKKNFEOXEAEC-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.7
• 重原子数：
  38
• 可旋转键数：
  6
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.17
• 拓扑面积：
  123
• 氢给体数：
  4
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  1-(3-tert-butyl-1-m-tolyl-1H-pyrazol-5-yl)-3-(3-(6-nitroquinazolin-4-ylamino)phenyl)urea 在 palladium on activated charcoal 、 甲酸铵 作用下， 以 乙醇 为溶剂， 反应 3.0h， 以36%的产率得到RL62
  参考文献：
  名称：

  Hybrid Compound Design To Overcome the Gatekeeper T338M Mutation in cSrc

  摘要：

  The emergence of drug resistance remains a fundamental challenge in the development of kinase inhibitors that are effective over long-term treatments. Allosteric inhibitors that bind to sites lying outside the highly conserved ATP pocket are thought to be more selective than ATP-competitive inhibitors and may circumvent some mechanisms of drug resistance. Crystal structures of type I and allosteric type III inhibitors in complex with the tyrosine kinase cSrc allowed us to employ principles of structure-based design to develop these scaffolds into potent type II kinase inhibitors. One of these compounds, 3c (RL46), disrupts FAK-mediated focal adhesions in cancer cells via direct inhibition of cSrc. Details gleaned from crystal structures revealed a key feature of a subset of these compounds, a surprising flexibility in the vicinity of the gatekeeper residue that allows these compounds to overcome a dasatinib-resistant gatekeeper mutation emerging in cSrc.

  DOI：

  10.1021/jm9002928