4-methyl-3-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)benzoic acid | 926277-89-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 英文名称: 4-methyl-3-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)benzoic acid
• 英文别名: 4-Methyl-3-[3-[2-(methylamino)pyrimidin-4-yl]pyridin-2-yl]oxybenzoic acid
• CAS: 926277-89-6
• 化学式: C₁₈H₁₆N₄O₃
• 分子量: 336.35
• InChiKey: AWOTXLQDVUPRKQ-UHFFFAOYSA-N

物化性质

• 沸点：
  581.1±60.0 °C(Predicted)
• 密度：
  1.328±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.9
• 重原子数：
  25
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.11
• 拓扑面积：
  97.2
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  4-methyl-3-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)benzoic acid 在 N,N-二甲基甲酰胺 草酰氯 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 反应 27.5h， 生成 4-甲基-3-[[3-[2-(甲基氨基)-4-嘧啶基]-2-吡啶基]氧基]-N-[3-(三氟甲基)苯基]苯甲酰胺
  参考文献：
  名称：

  Evolution of a Highly Selective and Potent 2-(Pyridin-2-yl)-1,3,5-triazine Tie-2 Kinase Inhibitor

  摘要：

  Inhibition of angiogenesis is a promising and clinically validated approach for limiting tumor growth and survival. The receptor tyrosine kinase Tie-2 is expressed almost exclusively in the vascular endothelium and is required for developmental angiogenesis and vessel maturation. However, the significance of Tie-2 signaling in tumor angiogenesis is not well understood. In order to evaluate the therapeutic utility of inhibiting Tie-2 signaling, we developed a series of potent and orally bioavailable small molecule Tie-2 kinase inhibitors with selectivity over other kinases, especially those that are believed to be important for tumor angiogenesis. Our earlier work provided pyridinyl pyrimidine 6 as a potent, nonselective Tie-2 inhibitor that was designed on the basis of X-ray cocrystal structures of KDR inhibitors 34 (triazine) and 35 (nicotinamide). Lead optimization resulted in pyridinyl triazine 63, which exhibited > 30-fold selectivity over a panel of kinases, good oral exposure, and in vivo inhibition of Tie-2 phosphorylation.

  DOI：

  10.1021/jm061107l
• 作为产物：
  描述：

  3-乙酰基-2-氯吡啶 在 sodium methylate 、 caesium carbonate 作用下， 以 甲醇 、 二甲基亚砜 为溶剂， 反应 41.0h， 生成 4-methyl-3-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)benzoic acid
  参考文献：
  名称：

  Evolution of a Highly Selective and Potent 2-(Pyridin-2-yl)-1,3,5-triazine Tie-2 Kinase Inhibitor

  摘要：

  Inhibition of angiogenesis is a promising and clinically validated approach for limiting tumor growth and survival. The receptor tyrosine kinase Tie-2 is expressed almost exclusively in the vascular endothelium and is required for developmental angiogenesis and vessel maturation. However, the significance of Tie-2 signaling in tumor angiogenesis is not well understood. In order to evaluate the therapeutic utility of inhibiting Tie-2 signaling, we developed a series of potent and orally bioavailable small molecule Tie-2 kinase inhibitors with selectivity over other kinases, especially those that are believed to be important for tumor angiogenesis. Our earlier work provided pyridinyl pyrimidine 6 as a potent, nonselective Tie-2 inhibitor that was designed on the basis of X-ray cocrystal structures of KDR inhibitors 34 (triazine) and 35 (nicotinamide). Lead optimization resulted in pyridinyl triazine 63, which exhibited > 30-fold selectivity over a panel of kinases, good oral exposure, and in vivo inhibition of Tie-2 phosphorylation.

  DOI：

  10.1021/jm061107l

文献信息

• Evolution of a Highly Selective and Potent 2-(Pyridin-2-yl)-1,3,5-triazine Tie-2 Kinase Inhibitor
  作者：Brian L. Hodous、Stephanie D. Geuns-Meyer、Paul E. Hughes、Brian K. Albrecht、Steve Bellon、James Bready、Sean Caenepeel、Victor J. Cee、Stuart C. Chaffee、Angela Coxon、Maurice Emery、Jenne Fretland、Paul Gallant、Yan Gu、Doug Hoffman、Rebecca E. Johnson、Richard Kendall、Joseph L. Kim、Alexander M. Long、Michael Morrison、Philip R. Olivieri、Vinod F. Patel、Anthony Polverino、Paul Rose、Paul Tempest、Ling Wang、Douglas A. Whittington、Huilin Zhao

  DOI：10.1021/jm061107l

  日期：2007.2.1

  Inhibition of angiogenesis is a promising and clinically validated approach for limiting tumor growth and survival. The receptor tyrosine kinase Tie-2 is expressed almost exclusively in the vascular endothelium and is required for developmental angiogenesis and vessel maturation. However, the significance of Tie-2 signaling in tumor angiogenesis is not well understood. In order to evaluate the therapeutic utility of inhibiting Tie-2 signaling, we developed a series of potent and orally bioavailable small molecule Tie-2 kinase inhibitors with selectivity over other kinases, especially those that are believed to be important for tumor angiogenesis. Our earlier work provided pyridinyl pyrimidine 6 as a potent, nonselective Tie-2 inhibitor that was designed on the basis of X-ray cocrystal structures of KDR inhibitors 34 (triazine) and 35 (nicotinamide). Lead optimization resulted in pyridinyl triazine 63, which exhibited > 30-fold selectivity over a panel of kinases, good oral exposure, and in vivo inhibition of Tie-2 phosphorylation.