1-Ethyl-8-(4-Ethylphenyl)-5-Methyl-1,5-Dihydropyrazolo[4,3-C][2,1]benzothiazine 4,4-Dioxide | 1426683-30-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并噻嗪类
• 英文名称: 1-Ethyl-8-(4-Ethylphenyl)-5-Methyl-1,5-Dihydropyrazolo[4,3-C][2,1]benzothiazine 4,4-Dioxide
• 英文别名: 1-ethyl-8-(4-ethylphenyl)-5-methylpyrazolo[4,3-c][2,1]benzothiazine 4,4-dioxide
• CAS: 1426683-30-8
• 化学式: C₂₀H₂₁N₃O₂S
• 分子量: 367.472
• InChiKey: LWMFYSSKMYKGNI-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.4
• 重原子数：
  26
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.25
• 拓扑面积：
  63.6
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  5-溴-2-[(甲基磺酰基)氨基]苯甲酸甲酯 在 palladium diacetate 、 sodium hydride 、 sodium carbonate 、 potassium carbonate 、 三苯基膦 作用下， 以 四氢呋喃 、 乙二醇二甲醚 、 水 、 N,N-二甲基甲酰胺 、 mineral oil 为溶剂， 反应 9.83h， 生成 1-Ethyl-8-(4-Ethylphenyl)-5-Methyl-1,5-Dihydropyrazolo[4,3-C][2,1]benzothiazine 4,4-Dioxide
  参考文献：
  名称：

  Discovery and characterization of novel allosteric FAK inhibitors

  摘要：

  Focal adhesion kinase (FAR) regulates cell survival and proliferation pathways. Here we report the discovery of a highly selective series of 1,5-dihydropyrazolo[4,3-c][2,1]benzothiazines that demonstrate a novel mode of allosteric inhibition of FAR. These compounds showed slow dissociation from unphosphorylated FAR and were noncompetitive with ATP after long preincubation. Co-crystal structural analysis revealed that the compounds target a novel allosteric site within the C-lobe of the kinase domain, which induces disruption of ATP pocket formation leading to the inhibition of kinase activity. The potency of allosteric inhibition was reduced by phosphorylation of FAR. Coupled SAR analysis revealed that N-substitution of the fused pyrazole is critical to achieve allosteric binding and high selectivity among kinases. (C) 2012 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2012.06.035

文献信息

• Discovery and characterization of novel allosteric FAK inhibitors
  作者：Misa Iwatani、Hidehisa Iwata、Atsutoshi Okabe、Robert J. Skene、Naoki Tomita、Yoko Hayashi、Yoshio Aramaki、David J. Hosfield、Akira Hori、Atsuo Baba、Hiroshi Miki

  DOI：10.1016/j.ejmech.2012.06.035

  日期：2013.3

  Focal adhesion kinase (FAR) regulates cell survival and proliferation pathways. Here we report the discovery of a highly selective series of 1,5-dihydropyrazolo[4,3-c][2,1]benzothiazines that demonstrate a novel mode of allosteric inhibition of FAR. These compounds showed slow dissociation from unphosphorylated FAR and were noncompetitive with ATP after long preincubation. Co-crystal structural analysis revealed that the compounds target a novel allosteric site within the C-lobe of the kinase domain, which induces disruption of ATP pocket formation leading to the inhibition of kinase activity. The potency of allosteric inhibition was reduced by phosphorylation of FAR. Coupled SAR analysis revealed that N-substitution of the fused pyrazole is critical to achieve allosteric binding and high selectivity among kinases. (C) 2012 Elsevier Masson SAS. All rights reserved.