N-[3-(6-phenyl-4-{[(1R)-1-phenylethyl]amino}furo[2,3-d]pyrimidin-5-yl)phenyl]prop-2-enamide | 1226549-45-6

• 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-[3-(6-phenyl-4-{[(1R)-1-phenylethyl]amino}furo[2,3-d]pyrimidin-5-yl)phenyl]prop-2-enamide
• 英文别名: N-[3-[6-phenyl-4-[[(1R)-1-phenylethyl]amino]furo[2,3-d]pyrimidin-5-yl]phenyl]prop-2-enamide
• CAS: 1226549-45-6
• 化学式: C₂₉H₂₄N₄O₂
• 分子量: 460.535
• InChiKey: GRLBXHULTTZEJM-LJQANCHMSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.2
• 重原子数：
  35
• 可旋转键数：
  7
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.07
• 拓扑面积：
  80
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  5-bromo-4-chloro-6-phenylfuro[2,3-d]pyrimidine 在 吡啶 、 盐酸 、 palladium diacetate 、 sodium carbonate 、 三乙胺 、 tin(ll) chloride 作用下， 以 1,4-二氧六环 、 乙醚 、 乙醇 、 水 为溶剂， 反应 8.0h， 生成 N-[3-(6-phenyl-4-{[(1R)-1-phenylethyl]amino}furo[2,3-d]pyrimidin-5-yl)phenyl]prop-2-enamide
  参考文献：
  名称：

  Discovery of a Furanopyrimidine-Based Epidermal Growth Factor Receptor Inhibitor (DBPR112) as a Clinical Candidate for the Treatment of Non-Small Cell Lung Cancer

  摘要：

  Epidermal growth factor receptor (EGFR)-targeted therapy in non-small cell lung cancer represents a breakthrough in the field of precision medicine. Previously, we have identified a lead compound, furanopyrimidine 2, which contains a (S)-2-phenylglycinol structure as a key fragment to inhibit EGFR However, compound 2 showed high clearance and poor oral bioavailability in its pharmacokinetics studies. In this work, we optimized compound 2 by scaffold hopping and exploiting the potent inhibitory activity of various warhead groups to obtain a clinical candidate, 78 (DBPR112), which not only displayed a potent inhibitory activity against EGFR(L858R/T790M) double mutations but also exhibited tenfold potency better than the third-generation inhibitor, osimertinib, against EGFR and HER2 exon 20 insertion mutations. Overall, pharmacokinetic improvement through lead-to-candidate optimization yielded fourfold oral AUC better that afatinib along with F = 41.5%, an encouraging safety profile, and significant antitumor efficacy in in vivo xenograft models. DBPR112 is currently undergoing phase 1 clinical trial in Taiwan.

  DOI：

  10.1021/acs.jmedchem.9b00722

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
• Discovery of a Furanopyrimidine-Based Epidermal Growth Factor Receptor Inhibitor (DBPR112) as a Clinical Candidate for the Treatment of Non-Small Cell Lung Cancer
  作者：Shu-Yu Lin、Yung Chang Hsu、Yi-Hui Peng、Yi-Yu Ke、Wen-Hsing Lin、Hsu-Yi Sun、Hui-Yi Shiao、Fu-Ming Kuo、Pei-Yi Chen、Tzu-Wen Lien、Chun-Hwa Chen、Chang-Ying Chu、Sing-Yi Wang、Kai-Chia Yeh、Ching-Ping Chen、Tsu-An Hsu、Su-Ying Wu、Teng-Kuang Yeh、Chiung-Tong Chen、Hsing-Pang Hsieh

  DOI：10.1021/acs.jmedchem.9b00722

  日期：2019.11.27

  Epidermal growth factor receptor (EGFR)-targeted therapy in non-small cell lung cancer represents a breakthrough in the field of precision medicine. Previously, we have identified a lead compound, furanopyrimidine 2, which contains a (S)-2-phenylglycinol structure as a key fragment to inhibit EGFR However, compound 2 showed high clearance and poor oral bioavailability in its pharmacokinetics studies. In this work, we optimized compound 2 by scaffold hopping and exploiting the potent inhibitory activity of various warhead groups to obtain a clinical candidate, 78 (DBPR112), which not only displayed a potent inhibitory activity against EGFR(L858R/T790M) double mutations but also exhibited tenfold potency better than the third-generation inhibitor, osimertinib, against EGFR and HER2 exon 20 insertion mutations. Overall, pharmacokinetic improvement through lead-to-candidate optimization yielded fourfold oral AUC better that afatinib along with F = 41.5%, an encouraging safety profile, and significant antitumor efficacy in in vivo xenograft models. DBPR112 is currently undergoing phase 1 clinical trial in Taiwan.