N-(3-(tert-butyl)-5-(2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪烷类
• 英文名称: N-(3-(tert-butyl)-5-(2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide
• 英文别名: N-[3-tert-butyl-5-[2-[2-methoxy-4-(4-methylpiperazin-1-yl)anilino]-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8-yl]phenyl]prop-2-enamide
• 化学式: C₃₃H₃₉N₇O₃
• 分子量: 581.718
• InChiKey: DUPITFFKOWXUEZ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.8
• 重原子数：
  43
• 可旋转键数：
  8
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  103
• 氢给体数：
  2
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  1,3-二溴-5-(1,1-二甲基乙基)苯 在 copper(I) oxide 、 sodium azide 、 potassium carbonate 、 二甲基亚砜 、 N,N-二异丙基乙胺 、 三氟乙酸 、 L-脯氨酸 作用下， 以 四氢呋喃 、 二氯甲烷 、 N,N-二甲基甲酰胺 、 仲丁醇 为溶剂， 反应 86.0h， 生成 N-(3-(tert-butyl)-5-(2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide
  参考文献：
  名称：

  A structure-guided optimization of pyrido[2,3-d]pyrimidin-7-ones as selective inhibitors of EGFRL858R/T790M mutant with improved pharmacokinetic properties

  摘要：

  Structural optimization of pyrido[2,3-d]pyrimidin-7-ones was conducted to yield a series of new selective EGFR(T790M) inhibitors with improved pharmacokinetic properties. One of the most promising compound 9s potently suppressed EGFR(L858R/T790M) kinase and inhibited the proliferation of H1975 cells with IC50 values of 2.0 nM and 40 nM, respectively. The compound dose-dependently induced reduction of the phosphorylation of EGFR and downstream activation of ERIC in NCI-H1975 cells. It also exhibited moderate plasma exposure after oral administration and an oral bioavailability value of 16%. Compound 9s may serve as a promising lead compound for further drug discovery overcoming the acquired resistance of non-small cell lung cancer (NSCLC) patients. (C) 2016 Published by Elsevier Masson SAS.

  DOI：

  10.1016/j.ejmech.2016.12.006

文献信息

• A structure-guided optimization of pyrido[2,3-d]pyrimidin-7-ones as selective inhibitors of EGFRL858R/T790M mutant with improved pharmacokinetic properties
  作者：Lei Yu、Minhao Huang、Tianfeng Xu、Linjiang Tong、Xiao-e Yan、Zhang Zhang、Yong Xu、Caihong Yun、Hua Xie、Ke Ding、Xiaoyun Lu

  DOI：10.1016/j.ejmech.2016.12.006

  日期：2017.1

  Structural optimization of pyrido[2,3-d]pyrimidin-7-ones was conducted to yield a series of new selective EGFR(T790M) inhibitors with improved pharmacokinetic properties. One of the most promising compound 9s potently suppressed EGFR(L858R/T790M) kinase and inhibited the proliferation of H1975 cells with IC50 values of 2.0 nM and 40 nM, respectively. The compound dose-dependently induced reduction of the phosphorylation of EGFR and downstream activation of ERIC in NCI-H1975 cells. It also exhibited moderate plasma exposure after oral administration and an oral bioavailability value of 16%. Compound 9s may serve as a promising lead compound for further drug discovery overcoming the acquired resistance of non-small cell lung cancer (NSCLC) patients. (C) 2016 Published by Elsevier Masson SAS.