8-(4-ethylphenyl)-5-methyl-1,5-dihydropyrazolo[4,3-c][2,1]benzothiazine 4,4-dioxide | 1426683-29-5

• 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: 8-(4-ethylphenyl)-5-methyl-1,5-dihydropyrazolo[4,3-c][2,1]benzothiazine 4,4-dioxide
• 英文别名: 8-(4-Ethylphenyl)-5-Methyl-2,5-Dihydropyrazolo[4,3-C][2,1]benzothiazine 4,4-Dioxide；8-(4-ethylphenyl)-5-methyl-1H-pyrazolo[4,3-c][2,1]benzothiazine 4,4-dioxide
• CAS: 1426683-29-5
• 化学式: C₁₈H₁₇N₃O₂S
• 分子量: 339.418
• InChiKey: ISXAVIPPPMJTPN-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  24
• 可旋转键数：
  2
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.17
• 拓扑面积：
  74.4
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  8-(4-ethylphenyl)-5-methyl-1,5-dihydropyrazolo[4,3-c][2,1]benzothiazine 4,4-dioxide 、 碘甲烷 在 potassium carbonate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 78.0h， 以81%的产率得到8-(4-Ethylphenyl)-2,5-dimethylpyrazolo[4,3-c][2,1]benzothiazine 4,4-dioxide
  参考文献：
  名称：

  Structure-based discovery of cellular-active allosteric inhibitors of FAK

  摘要：

  In order to develop potent and selective focal adhesion kinase (FAK) inhibitors, synthetic studies on pyrazolo[ 4,3-c][2,1]benzothiazines targeted for the FAK allosteric site were carried out. Based on the X-ray structural analysis of the co-crystal of the lead compound, 8-(4-ethylphenyl)-5-methyl-1,5-dihydropyrazolo[4,3-c][2,1]benzothiazine 4,4-dioxide 1 with FAK, we designed and prepared 1,5-dimethyl-1,5-dihydropyrazolo[4,3-c][2,1]benzothiazin derivatives which selectively inhibited kinase activity of FAK without affecting seven other kinases. The optimized compound, N-(4-tert-butylbenzyl)-1,5-dimethyl-1,5-dihydropyrazolo[4,3-c][2,1]benzothiazin-8-amine 4,4-dioxide 30 possessed significant FAK kinase inhibitory activities both in cell-free (IC50 = 0.64 mu M) and in cellular assays (IC50 = 7.1 mu M). These results clearly demonstrated a potential of FAK allosteric inhibitors as antitumor agents. (C) 2013 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2013.01.047
• 作为产物：
  描述：

  5-溴-2-[(甲基磺酰基)氨基]苯甲酸甲酯 在 3,4-二氢-2H-吡喃 、 sodium hydride 、 potassium carbonate 、 三氟乙酸 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 为溶剂， 反应 5.0h， 生成 8-(4-ethylphenyl)-5-methyl-1,5-dihydropyrazolo[4,3-c][2,1]benzothiazine 4,4-dioxide
  参考文献：
  名称：

  Structure-based discovery of cellular-active allosteric inhibitors of FAK

  摘要：

  In order to develop potent and selective focal adhesion kinase (FAK) inhibitors, synthetic studies on pyrazolo[ 4,3-c][2,1]benzothiazines targeted for the FAK allosteric site were carried out. Based on the X-ray structural analysis of the co-crystal of the lead compound, 8-(4-ethylphenyl)-5-methyl-1,5-dihydropyrazolo[4,3-c][2,1]benzothiazine 4,4-dioxide 1 with FAK, we designed and prepared 1,5-dimethyl-1,5-dihydropyrazolo[4,3-c][2,1]benzothiazin derivatives which selectively inhibited kinase activity of FAK without affecting seven other kinases. The optimized compound, N-(4-tert-butylbenzyl)-1,5-dimethyl-1,5-dihydropyrazolo[4,3-c][2,1]benzothiazin-8-amine 4,4-dioxide 30 possessed significant FAK kinase inhibitory activities both in cell-free (IC50 = 0.64 mu M) and in cellular assays (IC50 = 7.1 mu M). These results clearly demonstrated a potential of FAK allosteric inhibitors as antitumor agents. (C) 2013 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2013.01.047

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.
• Structure-based discovery of cellular-active allosteric inhibitors of FAK
  作者：Naoki Tomita、Yoko Hayashi、Shinkichi Suzuki、Yoshimasa Oomori、Yoshio Aramaki、Yoshihiro Matsushita、Misa Iwatani、Hidehisa Iwata、Atsutoshi Okabe、Yoshiko Awazu、Osamu Isono、Robert J. Skene、David J. Hosfield、Hiroshi Miki、Tomohiro Kawamoto、Akira Hori、Atsuo Baba

  DOI：10.1016/j.bmcl.2013.01.047

  日期：2013.3

  In order to develop potent and selective focal adhesion kinase (FAK) inhibitors, synthetic studies on pyrazolo[ 4,3-c][2,1]benzothiazines targeted for the FAK allosteric site were carried out. Based on the X-ray structural analysis of the co-crystal of the lead compound, 8-(4-ethylphenyl)-5-methyl-1,5-dihydropyrazolo[4,3-c][2,1]benzothiazine 4,4-dioxide 1 with FAK, we designed and prepared 1,5-dimethyl-1,5-dihydropyrazolo[4,3-c][2,1]benzothiazin derivatives which selectively inhibited kinase activity of FAK without affecting seven other kinases. The optimized compound, N-(4-tert-butylbenzyl)-1,5-dimethyl-1,5-dihydropyrazolo[4,3-c][2,1]benzothiazin-8-amine 4,4-dioxide 30 possessed significant FAK kinase inhibitory activities both in cell-free (IC50 = 0.64 mu M) and in cellular assays (IC50 = 7.1 mu M). These results clearly demonstrated a potential of FAK allosteric inhibitors as antitumor agents. (C) 2013 Elsevier Ltd. All rights reserved.