N-(4-(2-(4-methoxyphenylamino)-7-oxopteridin-8(7H)-yl)-phenyl)propionamide

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 蝶啶及其衍生物
• 英文名称: N-(4-(2-(4-methoxyphenylamino)-7-oxopteridin-8(7H)-yl)-phenyl)propionamide
• 英文别名: N-(4-(2-(4-methoxyphenylamino)-7-oxo-8(7H)-pteridinyl)phenyl) propionamide；N-[4-[2-(4-methoxyanilino)-7-oxopteridin-8-yl]phenyl]propanamide
• 化学式: C₂₂H₂₀N₆O₃
• 分子量: 416.439
• InChiKey: PUAZSJAPNIJEFA-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.6
• 重原子数：
  31
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.14
• 拓扑面积：
  109
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  特定基氨基甲酸脂酶 在 palladium 10% on activated carbon 、 氢气 、 溶剂黄146 、 三乙胺 、 N,N-二异丙基乙胺 、 三氟乙酸 作用下， 以 1,4-二氧六环 、 乙醇 、 二氯甲烷 、 甲苯 为溶剂， 20.0 ℃ 、206.85 kPa 条件下， 反应 44.0h， 生成 N-(4-(2-(4-methoxyphenylamino)-7-oxopteridin-8(7H)-yl)-phenyl)propionamide
  参考文献：
  名称：

  Discovery of Pteridin-7(8H)-one-Based Irreversible Inhibitors Targeting the Epidermal Growth Factor Receptor (EGFR) Kinase T790M/L858R Mutant

  摘要：

  The EGFR T790M variant is an important mutation, resulting in approximately 50% of the clinically acquired resistance to approved EGFR inhibitors. Starting with a previously reported pyrimidine-based EGFR inhibitor, a novel pteridin-7(8H)-one scaffold with a high 3D similarity was found and transformed into irreversible inhibitors of the EGFR T790M mutant. The most potent compounds, 3q and 3x, exhibited excellent enzyme inhibitory activities, with subnanomolar IC50 values for both the wild-type and T790M/L858R double mutant EGFRs, as well as potent cellular antiproliferative activities against both gefitinib-sensitive and -resistant cancer cell lines. The in vivo antitumor efficacy study demonstrated that compound 3x significantly inhibited tumor growth and induced tumor stasis in an EGFR-T790M/L858R-driven human nonsmall-cell lung cancer xenograft mouse model. This work demonstrated the utility of this sophisticated computational design strategy for fast 3D scaffold hopping with competitive bioactivities to meet an important clinical need.

  DOI：

  10.1021/jm401045n

文献信息

• PTERIDINE KETONE DERIVATIVE AND APPLICATIONS THEREOF AS EGFR, BLK, AND FLT3 INHIBITOR
  申请人：EAST CHINA UNIVERSITY OF SCIENCE AND TECHNOLOGY

  公开号：US20150126508A1

  公开（公告）日：2015-05-07

  Provided are a pteridine ketone derivative used as an EGFR, BLK, and FLT3 inhibitor and applications thereof. Specifically, provided are a compound of the following formula I, a pharmaceutical composition containing the compound of the formula I, and use of compound in preparing medicine for treating diseases mediated by EGFR, BLK, or FLT3 or inhibiting EGFR, BLK, and FLT3.

  提供了一种吡哌啶酮衍生物，用作EGFR、BLK和FLT3抑制剂及其应用。具体而言，提供了以下结构式I的化合物，含有该化合物的药物组合物，以及将该化合物用于制备治疗由EGFR、BLK或FLT3介导的疾病或抑制EGFR、BLK和FLT3的药物的用途。
• US9670213B2
  申请人：——

  公开号：US9670213B2

  公开（公告）日：2017-06-06
• Discovery of Pteridin-7(8<i>H</i>)-one-Based Irreversible Inhibitors Targeting the Epidermal Growth Factor Receptor (EGFR) Kinase T790M/L858R Mutant
  作者：Wei Zhou、Xiaofeng Liu、Zhengchao Tu、Lianwen Zhang、Xin Ku、Fang Bai、Zhenjiang Zhao、Yufang Xu、Ke Ding、Honglin Li

  DOI：10.1021/jm401045n

  日期：2013.10.24

  The EGFR T790M variant is an important mutation, resulting in approximately 50% of the clinically acquired resistance to approved EGFR inhibitors. Starting with a previously reported pyrimidine-based EGFR inhibitor, a novel pteridin-7(8H)-one scaffold with a high 3D similarity was found and transformed into irreversible inhibitors of the EGFR T790M mutant. The most potent compounds, 3q and 3x, exhibited excellent enzyme inhibitory activities, with subnanomolar IC50 values for both the wild-type and T790M/L858R double mutant EGFRs, as well as potent cellular antiproliferative activities against both gefitinib-sensitive and -resistant cancer cell lines. The in vivo antitumor efficacy study demonstrated that compound 3x significantly inhibited tumor growth and induced tumor stasis in an EGFR-T790M/L858R-driven human nonsmall-cell lung cancer xenograft mouse model. This work demonstrated the utility of this sophisticated computational design strategy for fast 3D scaffold hopping with competitive bioactivities to meet an important clinical need.