1-(4-(2-amino-3-nitropyridin-4-yloxy)-2-fluorophenyl)-3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)urea | 1234623-42-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 1-(4-(2-amino-3-nitropyridin-4-yloxy)-2-fluorophenyl)-3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)urea
• 英文别名: 1-[4-(2-Amino-3-nitropyridin-4-yl)oxy-2-fluorophenyl]-3-[5-tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]urea
• CAS: 1234623-42-7
• 化学式: C₂₆H₂₆FN₇O₄
• 分子量: 519.535
• InChiKey: BVWCSMTYTRWMDJ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.5
• 重原子数：
  38
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.19
• 拓扑面积：
  153
• 氢给体数：
  3
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  1-(4-(2-amino-3-nitropyridin-4-yloxy)-2-fluorophenyl)-3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)urea 在 palladium 10% on activated carbon 、 氢气 作用下， 以 乙醇 、 乙酸乙酯 为溶剂， 反应 3.0h， 以75%的产率得到1-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)-3-(4-(2,3-diaminopyridin-4-yloxy)-2-fluorophenyl)urea
  参考文献：
  名称：

  Novel Hinge Binder Improves Activity and Pharmacokinetic Properties of BRAF Inhibitors

  摘要：

  Mutated BRAF serine/threonine kinase is implicated in several types of cancer, with particularly high frequency in melanoma and colorectal carcinoma. We recently reported on the development of BRAF inhibitors based on a tripartite A B C system featuring art imidazo[4,5]pyridin-2-one group hinge binder. Here we present the design, synthesis, and optimization of a new series of inhibitors with a different A B C system that has been modified by the introduction of a range of novel hinge binders (A ring). The optimization of the hinge binding moiety has enabled the development of compounds with low nanomolar potencies in both BRAF inhibition and cellular assays. These compounds display optimal pharmacokinetic properties that warrant further in vivo investigations.

  DOI：

  10.1021/jm100383b
• 作为产物：
  描述：

  4-(4-amino-3-fluorophenoxy)-3-nitropyridin-2-amine 、 3-(tert-butyl)-5-isocyanato-1-(p-tolyl)-1H-pyrazole 以 四氢呋喃 为溶剂， 反应 0.53h， 以68%的产率得到1-(4-(2-amino-3-nitropyridin-4-yloxy)-2-fluorophenyl)-3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)urea
  参考文献：
  名称：

  Novel Hinge Binder Improves Activity and Pharmacokinetic Properties of BRAF Inhibitors

  摘要：

  Mutated BRAF serine/threonine kinase is implicated in several types of cancer, with particularly high frequency in melanoma and colorectal carcinoma. We recently reported on the development of BRAF inhibitors based on a tripartite A B C system featuring art imidazo[4,5]pyridin-2-one group hinge binder. Here we present the design, synthesis, and optimization of a new series of inhibitors with a different A B C system that has been modified by the introduction of a range of novel hinge binders (A ring). The optimization of the hinge binding moiety has enabled the development of compounds with low nanomolar potencies in both BRAF inhibition and cellular assays. These compounds display optimal pharmacokinetic properties that warrant further in vivo investigations.

  DOI：

  10.1021/jm100383b

文献信息

• Novel Hinge Binder Improves Activity and Pharmacokinetic Properties of BRAF Inhibitors
  作者：Alfonso Zambon、Delphine Ménard、Bart M. J. M. Suijkerbuijk、Ion Niculescu-Duvaz、Steven Whittaker、Dan Niculescu-Duvaz、Arnaud Nourry、Lawrence Davies、Helen A. Manne、Filipa Lopes、Natasha Preece、Douglas Hedley、Lesley M. Ogilvie、Ruth Kirk、Richard Marais、Caroline J. Springer

  DOI：10.1021/jm100383b

  日期：2010.8.12

  Mutated BRAF serine/threonine kinase is implicated in several types of cancer, with particularly high frequency in melanoma and colorectal carcinoma. We recently reported on the development of BRAF inhibitors based on a tripartite A B C system featuring art imidazo[4,5]pyridin-2-one group hinge binder. Here we present the design, synthesis, and optimization of a new series of inhibitors with a different A B C system that has been modified by the introduction of a range of novel hinge binders (A ring). The optimization of the hinge binding moiety has enabled the development of compounds with low nanomolar potencies in both BRAF inhibition and cellular assays. These compounds display optimal pharmacokinetic properties that warrant further in vivo investigations.