4-fluoro-2-(2-fluoro-4-iodoanilino)-6-(1H-indazol-6-yloxy)benzamide | 1429193-11-2

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 4-fluoro-2-(2-fluoro-4-iodoanilino)-6-(1H-indazol-6-yloxy)benzamide
• CAS: 1429193-11-2
• 化学式: C₂₀H₁₃F₂IN₄O₂
• 分子量: 506.25
• InChiKey: UVTXWUYDGCBNOT-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.9
• 重原子数：
  29
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  93
• 氢给体数：
  3
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  2-氟-4-碘苯胺 在 caesium carbonate 、 lithium hexamethyldisilazane 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 为溶剂， 生成 4-fluoro-2-(2-fluoro-4-iodoanilino)-6-(1H-indazol-6-yloxy)benzamide
  参考文献：
  名称：

  Optimization of allosteric MEK inhibitors. Part 1: Venturing into underexplored SAR territories

  摘要：

  Using PD325901 as a starting point for identifying novel allosteric MEK inhibitors with high cell potency and long-lasting target inhibition in vivo, truncation of its hydroxamic ester headgroup was combined with incorporation of alkyl and aryl ethers at the neighboring ring position. Whereas alkoxy side chains did not yield sufficient levels of cell potency, specifically substituted aryloxy groups allowed for high enzymatic and cellular potencies. Sulfamide 28 was identified as a highly potent MEK inhibitor with nanomolar cell potency against B-RAF (V600E) as well as Ras-mutated cell lines, high metabolic stability and resulting long half-lives. It was efficacious against B-RAF as well as K-Ras driven xenograft models and showed-despite being orally bioavailable and not a P-glycoprotein substrate-much lower brain/plasma exposure ratios than PD325901. (C) 2013 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2013.02.028

文献信息

• Optimization of allosteric MEK inhibitors. Part 1: Venturing into underexplored SAR territories
  作者：Ingo V. Hartung、Marion Hitchcock、Florian Pühler、Roland Neuhaus、Arne Scholz、Stefanie Hammer、Kirstin Petersen、Gerhard Siemeister、Dominic Brittain、Roman C. Hillig

  DOI：10.1016/j.bmcl.2013.02.028

  日期：2013.4

  Using PD325901 as a starting point for identifying novel allosteric MEK inhibitors with high cell potency and long-lasting target inhibition in vivo, truncation of its hydroxamic ester headgroup was combined with incorporation of alkyl and aryl ethers at the neighboring ring position. Whereas alkoxy side chains did not yield sufficient levels of cell potency, specifically substituted aryloxy groups allowed for high enzymatic and cellular potencies. Sulfamide 28 was identified as a highly potent MEK inhibitor with nanomolar cell potency against B-RAF (V600E) as well as Ras-mutated cell lines, high metabolic stability and resulting long half-lives. It was efficacious against B-RAF as well as K-Ras driven xenograft models and showed-despite being orally bioavailable and not a P-glycoprotein substrate-much lower brain/plasma exposure ratios than PD325901. (C) 2013 Elsevier Ltd. All rights reserved.