N-[4-(4-{[(1S)-2-hydroxy-1-phenylethyl]amino}6-phenylfuro[2,3-d]pyrimidin-5-yl)phenyl]acetamide | 1226548-45-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 呋喃
• 英文名称: N-[4-(4-{[(1S)-2-hydroxy-1-phenylethyl]amino}6-phenylfuro[2,3-d]pyrimidin-5-yl)phenyl]acetamide
• 英文别名: N-[4-[4-[[(1S)-2-hydroxy-1-phenylethyl]amino]-6-phenylfuro[2,3-d]pyrimidin-5-yl]phenyl]acetamide
• CAS: 1226548-45-3
• 化学式: C₂₈H₂₄N₄O₃
• 分子量: 464.524
• InChiKey: BMSYYYVQJGFDHW-HSZRJFAPSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.6
• 重原子数：
  35
• 可旋转键数：
  7
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.11
• 拓扑面积：
  100
• 氢给体数：
  3
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  4-氯-5,6-二苯基呋喃并[2,3-D]嘧啶 在 (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride 、 N-溴代丁二酰亚胺(NBS) 、 sodium carbonate 、 三乙胺 作用下， 以 1,4-二氧六环 、 乙醇 、 水 为溶剂， 反应 2.0h， 生成 N-[4-(4-{[(1S)-2-hydroxy-1-phenylethyl]amino}6-phenylfuro[2,3-d]pyrimidin-5-yl)phenyl]acetamide
  参考文献：
  名称：

  Protein Kinase Inhibitor Design by Targeting the Asp-Phe-Gly (DFG) Motif: The Role of the DFG Motif in the Design of Epidermal Growth Factor Receptor Inhibitors

  摘要：

  The Asp-Phe-Gly (DFG) motif plays an important role in the regulation of kinase activity. Structure-based drug design was performed to design compounds able to interact with the DFG motif; epidermal growth factor receptor (EGFR) was selected as an example. Structural insights obtained from the EGFR/2a complex suggested that an extension from the meta-position on the phenyl group (ring-5) would improve interactions with the DFG motif. Indeed, introduction of an N,N-dimethylamino tail resulted in 4b, which showed almost 50-fold improvement in inhibition compared to 2a. Structural studies confirmed this N,N-dimethylamino tail moved toward the DFG motif to form a salt bridge with the side chain of Asp831. That the interactions with the DFG motif greatly contribute to the potency of 4b is strongly evidenced by synthesizing and testing compounds 2a, 3g, and 4f: when the charge interactions are absent, the inhibitory activity decreased significantly.

  DOI：

  10.1021/jm400072p

文献信息

• Fused Bicyclic and Tricyclic Pyrimidine Compounds as Tyrosine Kinase Inhibitors
  申请人：Hsieh Hsing-Pang

  公开号：US20100120805A1

  公开（公告）日：2010-05-13

  Fused bicyclic or tricyclic compounds of formula (I): wherein A, B, C, X, Y, m, and n are defined herein. Also disclosed are a method for inhibiting EGFR kinase activity and a method for treating cancer with these compounds.

  式(I)的融合双环或三环化合物： 其中A、B、C、X、Y、m和n在此处定义。还公开了一种抑制EGFR激酶活性的方法以及使用这些化合物治疗癌症的方法。
• US8507502B2
  申请人：——

  公开号：US8507502B2

  公开（公告）日：2013-08-13
• [EN] FUSED BICYCLIC AND TRICYCLIC PYRIMIDINE COMPOUNDS AS TYROSINE KINASE INHIBITORS<br/>[FR] COMPOSÉS DE PYRIMIDINE BICYCLIQUES ET TRICYCLIQUES CONDENSÉS À TITRE D'INHIBITEURS DE TYROSINE KINASE
  申请人：NAT HEALTH RESEARCH INSTITUTES

  公开号：WO2010054285A2

  公开（公告）日：2010-05-14

  Fused bicyclic or tricyclic compounds of formula (I) defined herein are disclosed. Also disclosed are a method for inhibiting EGFR kinase activity and a method for treating cancer with these compounds.
• Protein Kinase Inhibitor Design by Targeting the Asp-Phe-Gly (DFG) Motif: The Role of the DFG Motif in the Design of Epidermal Growth Factor Receptor Inhibitors
  作者：Yi-Hui Peng、Hui-Yi Shiao、Chih-Hsiang Tu、Pang-Min Liu、John Tsu-An Hsu、Prashanth Kumar Amancha、Jian-Sung Wu、Mohane Selvaraj Coumar、Chun-Hwa Chen、Sing-Yi Wang、Wen-Hsing Lin、Hsu-Yi Sun、Yu-Sheng Chao、Ping-Chiang Lyu、Hsing-Pang Hsieh、Su-Ying Wu

  DOI：10.1021/jm400072p

  日期：2013.5.23

  The Asp-Phe-Gly (DFG) motif plays an important role in the regulation of kinase activity. Structure-based drug design was performed to design compounds able to interact with the DFG motif; epidermal growth factor receptor (EGFR) was selected as an example. Structural insights obtained from the EGFR/2a complex suggested that an extension from the meta-position on the phenyl group (ring-5) would improve interactions with the DFG motif. Indeed, introduction of an N,N-dimethylamino tail resulted in 4b, which showed almost 50-fold improvement in inhibition compared to 2a. Structural studies confirmed this N,N-dimethylamino tail moved toward the DFG motif to form a salt bridge with the side chain of Asp831. That the interactions with the DFG motif greatly contribute to the potency of 4b is strongly evidenced by synthesizing and testing compounds 2a, 3g, and 4f: when the charge interactions are absent, the inhibitory activity decreased significantly.