2-amino-5-(2-methoxyphenyl)furan-3-carbonitrile

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯酚醚
• 英文名称: 2-amino-5-(2-methoxyphenyl)furan-3-carbonitrile
• 英文别名: 2-Amino-5-(2-methoxyphenyl)furan-3-carbonitrile
• 化学式: C₁₂H₁₀N₂O₂
• 分子量: 214.224
• InChiKey: VSVMCOXSYJHRMO-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.5
• 重原子数：
  16
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.08
• 拓扑面积：
  72.2
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  2-amino-5-(2-methoxyphenyl)furan-3-carbonitrile 在 乙酸酐 、 三氯氧磷 作用下， 反应 6.0h， 生成 4-chloro-6-(2-methoxyphenyl)furo[2,3-d]pyrimidine
  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
• 作为产物：
  描述：

  邻甲氧基-2-溴苯乙酮 、 丙二腈 在 二乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 5.17h， 以48%的产率得到2-amino-5-(2-methoxyphenyl)furan-3-carbonitrile
  参考文献：
  名称：

  Chiral 6-aryl-furo[2,3-d]pyrimidin-4-amines as EGFR inhibitors

  摘要：

  Epidermal growth factor receptor inhibitors are of importance in cancer therapy and possibly in the management of pain. Herein, we report a structure-activity relationship study with 29 new 6-aryl-furo [2,3-d]pyrimidin-4-amines, involving modification of the 4-amino group and 6-aryl function. The EGFR activity was especially dependent on having a chiral 4-benzylamino group with correct stereochemistry. Molecular dynamics indicate this to be due to favourable cation-pi interactions. The most active inhibitor identified, equipotent to Erlotinib, was substituted with (R)-1-phenylethylamine at C-4 and a N-1, N-1-dimethyl-1,2-diamine group in para position of the 6-aryl moiety. These new furopyrimidines had a different off-target kinase profile when compared to Erlotinib, and also possessed high activity towards Ba/F3 EGFR(L858R) reporter cells. Further, comparing the EGFR data of the furo[2,3-d]pyrimidin-4-amines with that of the corresponding thieno- and pyrrolopyrimidines concludes the furopyrimidine scaffold to be highly useful for development of new epidermal growth factor receptor antagonists. (C) 2016 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2016.04.054

文献信息

• Chiral 6-aryl-furo[2,3-d]pyrimidin-4-amines as EGFR inhibitors
  作者：Jin Han、Svein Jacob Kaspersen、Sondre Nervik、Kristin G. Nørsett、Eirik Sundby、Bård Helge Hoff

  DOI：10.1016/j.ejmech.2016.04.054

  日期：2016.8

  Epidermal growth factor receptor inhibitors are of importance in cancer therapy and possibly in the management of pain. Herein, we report a structure-activity relationship study with 29 new 6-aryl-furo [2,3-d]pyrimidin-4-amines, involving modification of the 4-amino group and 6-aryl function. The EGFR activity was especially dependent on having a chiral 4-benzylamino group with correct stereochemistry. Molecular dynamics indicate this to be due to favourable cation-pi interactions. The most active inhibitor identified, equipotent to Erlotinib, was substituted with (R)-1-phenylethylamine at C-4 and a N-1, N-1-dimethyl-1,2-diamine group in para position of the 6-aryl moiety. These new furopyrimidines had a different off-target kinase profile when compared to Erlotinib, and also possessed high activity towards Ba/F3 EGFR(L858R) reporter cells. Further, comparing the EGFR data of the furo[2,3-d]pyrimidin-4-amines with that of the corresponding thieno- and pyrrolopyrimidines concludes the furopyrimidine scaffold to be highly useful for development of new epidermal growth factor receptor antagonists. (C) 2016 Elsevier Masson SAS. All rights reserved.
• 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.