3-(3,4-dimethoxyphenyl)-N5-(3-(dimethylamino)propyl)-6-phenylpyrazolo[1,5-a]pyrimidine-5,7-diamine

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡唑并嘧啶类
• 英文名称: 3-(3,4-dimethoxyphenyl)-N5-(3-(dimethylamino)propyl)-6-phenylpyrazolo[1,5-a]pyrimidine-5,7-diamine
• 英文别名: 3-(3,4-dimethoxyphenyl)-5-N-[3-(dimethylamino)propyl]-6-phenylpyrazolo[1,5-a]pyrimidine-5,7-diamine
• 化学式: C₂₅H₃₀N₆O₂
• 分子量: 446.552
• InChiKey: ZHPRBIFEDSMSRL-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.03
• 重原子数：
  33.0
• 可旋转键数：
  9.0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.28
• 拓扑面积：
  89.94
• 氢给体数：
  2.0
• 氢受体数：
  8.0

反应信息

• 作为产物：
  描述：

  3,4-二甲氧基苯乙腈 在 ammonium hydroxide 、 三正丁胺 、 sodium ethanolate 、 sodium hydride 、 溶剂黄146 、 N,N-二甲基苯胺 、 肼 、 三氯氧磷 作用下， 以 四氢呋喃 、 乙醇 、 N,N-二甲基乙酰胺 、 水 、 mineral oil 为溶剂， 反应 96.17h， 生成 3-(3,4-dimethoxyphenyl)-N5-(3-(dimethylamino)propyl)-6-phenylpyrazolo[1,5-a]pyrimidine-5,7-diamine
  参考文献：
  名称：

  Efficacy and Tolerability of Pyrazolo[1,5-a]pyrimidine RET Kinase Inhibitors for the Treatment of Lung Adenocarcinoma

  摘要：

  RET (REarranged during Transfection) kinase gain-of-function aberrancies have been identified as potential oncogenic drivers in lung adenocarcinoma, along with several other cancer types, prompting the discovery and assessment of selective inhibitors. Internal mining and analysis of relevant kinase data informed the decision to investigate a pyrazolo[1,5-a]pyrimidine scaffold, where subsequent optimization led to the identification of compound WF-47-JS03 (1), a potent RET kinase inhibitor with >500-fold selectivity against KDR (Kinase insert Domain Receptor) in cellular assays. In subsequent mouse in vivo studies, compound 1 demonstrated effective brain penetration and was found to induce strong regression of RET-driven tumor xenografts at a well-tolerated dose (10 mg/kg, po, qd). Higher doses of 1, however, were poorly tolerated in mice, similar to other pyrazolo[1,5-a]pyrimidine compounds at or near the efficacious dose, and indicative of the narrow therapeutic windows seen with this scaffold.

  DOI：

  10.1021/acsmedchemlett.0c00015

文献信息

• Efficacy and Tolerability of Pyrazolo[1,5-<i>a</i>]pyrimidine RET Kinase Inhibitors for the Treatment of Lung Adenocarcinoma
  作者：Casey J. N. Mathison、Donatella Chianelli、Paul V. Rucker、John Nelson、Jason Roland、Zhihong Huang、Yang Yang、Jiqing Jiang、Yun Feng Xie、Robert Epple、Badry Bursulaya、Christian Lee、Mu-Yun Gao、Jennifer Shaffer、Sergio Briones、Yelena Sarkisova、Anna Galkin、Lintong Li、Nanxin Li、Chun Li、Su Hua、Shailaja Kasibhatla、Jacqueline Kinyamu-Akunda、Rie Kikkawa、Valentina Molteni、John E. Tellew

  DOI：10.1021/acsmedchemlett.0c00015

  日期：2020.4.9

  RET (REarranged during Transfection) kinase gain-of-function aberrancies have been identified as potential oncogenic drivers in lung adenocarcinoma, along with several other cancer types, prompting the discovery and assessment of selective inhibitors. Internal mining and analysis of relevant kinase data informed the decision to investigate a pyrazolo[1,5-a]pyrimidine scaffold, where subsequent optimization led to the identification of compound WF-47-JS03 (1), a potent RET kinase inhibitor with >500-fold selectivity against KDR (Kinase insert Domain Receptor) in cellular assays. In subsequent mouse in vivo studies, compound 1 demonstrated effective brain penetration and was found to induce strong regression of RET-driven tumor xenografts at a well-tolerated dose (10 mg/kg, po, qd). Higher doses of 1, however, were poorly tolerated in mice, similar to other pyrazolo[1,5-a]pyrimidine compounds at or near the efficacious dose, and indicative of the narrow therapeutic windows seen with this scaffold.