4-(7-methoxy-6-{[2-(trimethylsilyl)ethoxy]methoxy}-1,4-dihydroindeno[1,2-c]pyrazol-3-yl)benzonitrile | 760992-64-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 4-(7-methoxy-6-{[2-(trimethylsilyl)ethoxy]methoxy}-1,4-dihydroindeno[1,2-c]pyrazol-3-yl)benzonitrile
• 英文别名: 4-[7-Methoxy-6-(2-trimethylsilylethoxymethoxy)-1,4-dihydroindeno[1,2-c]pyrazol-3-yl]benzonitrile
• CAS: 760992-64-1
• 化学式: C₂₄H₂₇N₃O₃Si
• 分子量: 433.582
• InChiKey: ORPDVAJBQIIVBE-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.22
• 重原子数：
  31
• 可旋转键数：
  8
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  80.2
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  4-(7-methoxy-6-{[2-(trimethylsilyl)ethoxy]methoxy}-1,4-dihydroindeno[1,2-c]pyrazol-3-yl)benzonitrile 、 2-(三甲基硅烷基)乙氧甲基氯 在 sodium hydride 、 盐酸 作用下， 以 N,N-二甲基甲酰胺 、 1,4-二氧六环 为溶剂， 生成 4-(6-Hydroxy-7-methoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-benzonitrile
  参考文献：
  名称：

  Discovery of 4′-(1,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-benzonitriles and 4′-(1,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-pyridine-2′-carbonitriles as potent checkpoint kinase 1 (Chk1) inhibitors

  摘要：

  An extensive structure-activity relationship study of the 3-position of a series of tricyclic pyrazole-based Chk1 inhibitors is described. As a result, 4'-,1,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-benzonitriles (4) and 4'-(1,4-dihydro-indeno[1,2-c]pyrazol-3-yl)pyridine-2'-carbonitriles (29) emerged as new lead series. Compared with the original lead compound 2, these new leads fully retain the biological activity in both enzymatic inhibition and cell-based assays. More importantly, the new leads 4 and 29 exhibit favorable physicochemical properties such as lower molecular weight, lower Clog P, and the absence of a hydroxyl group. Furthermore, structure-activity relationship studies were performed at the 6- and 7-positions of 4, which led to the identification of ideal Chk1 inhibitors 49, 50, 51, and 55. These compounds not only potently inhibit Chk1 in an enzymatic assay but also significantly potentiate the cytotoxicity of DNA-damaging agents in cell-based assays while they show little single agent activity. A cell cycle analysis by FACS confirmed that these Chk1 inhibitors efficiently abrogate the G2/M and S checkpoints induced by DNA-damaging agent. The current work paved the way to the identification of several potent Chk1 inhibitors with good pharmacokinetics that are suitable for in vivo study with oral dosing. (c) 2007 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2007.07.102
• 作为产物：
  描述：

  4-[(6-methoxy-1-oxo-5-{[2-(trimethylsilyl)ethoxy]methoxy}-2,3-dihydro-1H-inden-2-yl)carbonyl]benzonitrile 在 溶剂黄146 、 肼 作用下， 以 乙醇 为溶剂， 生成 4-(7-methoxy-6-{[2-(trimethylsilyl)ethoxy]methoxy}-1,4-dihydroindeno[1,2-c]pyrazol-3-yl)benzonitrile
  参考文献：
  名称：

  Discovery of 4′-(1,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-benzonitriles and 4′-(1,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-pyridine-2′-carbonitriles as potent checkpoint kinase 1 (Chk1) inhibitors

  摘要：

  An extensive structure-activity relationship study of the 3-position of a series of tricyclic pyrazole-based Chk1 inhibitors is described. As a result, 4'-,1,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-benzonitriles (4) and 4'-(1,4-dihydro-indeno[1,2-c]pyrazol-3-yl)pyridine-2'-carbonitriles (29) emerged as new lead series. Compared with the original lead compound 2, these new leads fully retain the biological activity in both enzymatic inhibition and cell-based assays. More importantly, the new leads 4 and 29 exhibit favorable physicochemical properties such as lower molecular weight, lower Clog P, and the absence of a hydroxyl group. Furthermore, structure-activity relationship studies were performed at the 6- and 7-positions of 4, which led to the identification of ideal Chk1 inhibitors 49, 50, 51, and 55. These compounds not only potently inhibit Chk1 in an enzymatic assay but also significantly potentiate the cytotoxicity of DNA-damaging agents in cell-based assays while they show little single agent activity. A cell cycle analysis by FACS confirmed that these Chk1 inhibitors efficiently abrogate the G2/M and S checkpoints induced by DNA-damaging agent. The current work paved the way to the identification of several potent Chk1 inhibitors with good pharmacokinetics that are suitable for in vivo study with oral dosing. (c) 2007 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2007.07.102

文献信息

• Discovery of 4′-(1,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-benzonitriles and 4′-(1,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-pyridine-2′-carbonitriles as potent checkpoint kinase 1 (Chk1) inhibitors
  作者：Zhi-Fu Tao、Gaoquan Li、Yunsong Tong、Kent D. Stewart、Zehan Chen、Mai-Ha Bui、Philip Merta、Chang Park、Peter Kovar、Haiying Zhang、Hing L. Sham、Saul H. Rosenberg、Thomas J. Sowin、Nan-Horng Lin

  DOI：10.1016/j.bmcl.2007.07.102

  日期：2007.11

  An extensive structure-activity relationship study of the 3-position of a series of tricyclic pyrazole-based Chk1 inhibitors is described. As a result, 4'-,1,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-benzonitriles (4) and 4'-(1,4-dihydro-indeno[1,2-c]pyrazol-3-yl)pyridine-2'-carbonitriles (29) emerged as new lead series. Compared with the original lead compound 2, these new leads fully retain the biological activity in both enzymatic inhibition and cell-based assays. More importantly, the new leads 4 and 29 exhibit favorable physicochemical properties such as lower molecular weight, lower Clog P, and the absence of a hydroxyl group. Furthermore, structure-activity relationship studies were performed at the 6- and 7-positions of 4, which led to the identification of ideal Chk1 inhibitors 49, 50, 51, and 55. These compounds not only potently inhibit Chk1 in an enzymatic assay but also significantly potentiate the cytotoxicity of DNA-damaging agents in cell-based assays while they show little single agent activity. A cell cycle analysis by FACS confirmed that these Chk1 inhibitors efficiently abrogate the G2/M and S checkpoints induced by DNA-damaging agent. The current work paved the way to the identification of several potent Chk1 inhibitors with good pharmacokinetics that are suitable for in vivo study with oral dosing. (c) 2007 Elsevier Ltd. All rights reserved.