5-fluoro-N-(4-(3-(2-methylaminopyrimidin-4-yl)pyridin-2-yloxy)phenyl)-2-phenylaminobenzamide | 1239702-58-9

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 5-fluoro-N-(4-(3-(2-methylaminopyrimidin-4-yl)pyridin-2-yloxy)phenyl)-2-phenylaminobenzamide
• 英文别名: 5-Fluoro-N-(4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)-2-(phenylamino)benzamide；2-anilino-5-fluoro-N-[4-[3-[2-(methylamino)pyrimidin-4-yl]pyridin-2-yl]oxyphenyl]benzamide
• CAS: 1239702-58-9
• 化学式: C₂₉H₂₃FN₆O₂
• 分子量: 506.539
• InChiKey: NVRFIADOENNEKV-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6
• 重原子数：
  38
• 可旋转键数：
  8
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.03
• 拓扑面积：
  101
• 氢给体数：
  3
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  4-(2-(4-aminophenoxy)pyridin-3-yl)-N-methylpyrimidin-2-amine 、 5-Fluor-N-phenyl-anthranilsaeure 在 N,N-二异丙基乙胺 、 Methanaminium,N-[(dimethylamino)(3H-1,2,3-triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methyl-, hexafluorophosphate(1-) 作用下， 以 氯仿 为溶剂， 反应 5.0h， 以40%的产率得到5-fluoro-N-(4-(3-(2-methylaminopyrimidin-4-yl)pyridin-2-yloxy)phenyl)-2-phenylaminobenzamide
  参考文献：
  名称：

  Discovery of a Potent, Selective, and Orally Bioavailable Pyridinyl-Pyrimidine Phthalazine Aurora Kinase Inhibitor

  摘要：

  The discovery of aurora kinases as essential regulators of cell division has led to intense interest in identifying small molecule aurora kinase inhibitors for the potential treatment of cancer. A high-throughput screening effort identified pyridinyl-pyrimidine 6a as a moderately potent dual inhibitor of aurora kinases -A and -B. Optimization of this hit resulted in an anthranilamide lead (6j) that possessed improved enzyme and cellular activity and exhibited a high level of kinase selectivity. However, this anthranilamide and subsequent analogues suffered from a lack of oral bioavailability. Converting the internally hydrogen-bonded six-membered pseudo-ring of the anthranilamide to a phthalazine (8a-b) led to a dramatic improvement in oral bioavailability (38-61%F) while maintaining the potency and selectivity characteristics of the anthranilamide series. In a COLO 205 tumor pharmacodynamic assay measuring phosphorylation of the aurora-B substrate histone H3 at serine 10 (p-histone H3), oral administration of 86 at 50 mg/kg demonstrated significant reduction in tumor p-histone H3 for at least 6 h.

  DOI：

  10.1021/jm100394y

文献信息

• Discovery of a Potent, Selective, and Orally Bioavailable Pyridinyl-Pyrimidine Phthalazine Aurora Kinase Inhibitor
  作者：Victor J. Cee、Laurie B. Schenkel、Brian L. Hodous、Holly L. Deak、Hanh N. Nguyen、Philip R. Olivieri、Karina Romero、Annette Bak、Xuhai Be、Steve Bellon、Tammy L. Bush、Alan C. Cheng、Grace Chung、Steve Coats、Patrick M. Eden、Kelly Hanestad、Paul L. Gallant、Yan Gu、Xin Huang、Richard L. Kendall、Min-Hwa Jasmine Lin、Michael J. Morrison、Vinod F. Patel、Robert Radinsky、Paul E. Rose、Sandra Ross、Ji-Rong Sun、Jin Tang、Huilin Zhao、Marc Payton、Stephanie D. Geuns-Meyer

  DOI：10.1021/jm100394y

  日期：2010.9.9

  The discovery of aurora kinases as essential regulators of cell division has led to intense interest in identifying small molecule aurora kinase inhibitors for the potential treatment of cancer. A high-throughput screening effort identified pyridinyl-pyrimidine 6a as a moderately potent dual inhibitor of aurora kinases -A and -B. Optimization of this hit resulted in an anthranilamide lead (6j) that possessed improved enzyme and cellular activity and exhibited a high level of kinase selectivity. However, this anthranilamide and subsequent analogues suffered from a lack of oral bioavailability. Converting the internally hydrogen-bonded six-membered pseudo-ring of the anthranilamide to a phthalazine (8a-b) led to a dramatic improvement in oral bioavailability (38-61%F) while maintaining the potency and selectivity characteristics of the anthranilamide series. In a COLO 205 tumor pharmacodynamic assay measuring phosphorylation of the aurora-B substrate histone H3 at serine 10 (p-histone H3), oral administration of 86 at 50 mg/kg demonstrated significant reduction in tumor p-histone H3 for at least 6 h.