6-(2-chloro-4-(6-methylpyrazin-2-yl)phenyl)-N-methyl-1H-indazole-3-carboxamide

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并吡唑类
• 英文名称: 6-(2-chloro-4-(6-methylpyrazin-2-yl)phenyl)-N-methyl-1H-indazole-3-carboxamide
• 英文别名: 6-[2-chloro-4-(6-methylpyrazin-2-yl)phenyl]-N-methyl-1H-indazole-3-carboxamide
• 化学式: C₂₀H₁₆ClN₅O
• 分子量: 377.833
• InChiKey: QIQJAZDVYCQJLU-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.3
• 重原子数：
  27
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.1
• 拓扑面积：
  83.6
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  2-(4-溴苯基)-2-氧代乙酸 在 盐酸 、 氯化亚砜 、 potassium carbonate 、 对甲苯磺酸 、 N,N-二异丙基乙胺 、 Methanaminium,N-[(dimethylamino)(3H-1,2,3-triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methyl-, hexafluorophosphate(1-) 、 sodium hydroxide 、 sodium nitrite 作用下， 以 1,4-二氧六环 、 甲醇 、 水 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 反应 35.0h， 生成 6-(2-chloro-4-(6-methylpyrazin-2-yl)phenyl)-N-methyl-1H-indazole-3-carboxamide
  参考文献：
  名称：

  Design and synthesis of 1H-indazole-3-carboxamide derivatives as potent and selective PAK1 inhibitors with anti-tumour migration and invasion activities

  摘要：

  Aberrant activation of p21-activated kinase 1 (PAK1) is associated with tumour progression, and PAK1 has been recognized as a promising target for anticancer drug discovery. However, the development of potent PAK1 inhibitors with satisfactory kinase selectivity and favourable physicochemical properties remains a daunting challenge. Herein, we identified the 1H-indazole-3-carboxamide derivatives as potential PAK1 inhibitors using a fragment-based screening approach. The representative compound 301 exhibited excellent enzyme inhibition (PAK1 IC50 = 9.8 nM) and high PAK1 selectivity toward a panel of 29 kinases. The Structure-activity relationship (SAR) analysis showed that substituting of an appropriate hydrophobic ring in the deep back pocket and introducing a hydrophilic group in the bulk solvent region were critical for PAK1 inhibitory activity and selectivity. Additionally, the hERG channel activity of 301 demonstrated its low risk of hERG toxicity. Furthermore, it significantly suppressed the migration and invasion of MDA-MB-231 cells by downregulating Snail expression without affecting the tumour growth. These results provide a new type of chemical scaffolds targeting PAK1 and suggested that 1H-indazole-3-carboxamide derivatives may serve as lead compounds for the development of potential and selective PAK1 inhibitors. (C) 2020 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2020.112517

文献信息

• Design and synthesis of 1H-indazole-3-carboxamide derivatives as potent and selective PAK1 inhibitors with anti-tumour migration and invasion activities
  作者：Mingliang Zhang、Xiaobao Fang、Cong Wang、Yi Hua、Chen Huang、Meng Wang、Lu Zhu、Zixu Wang、Yuhan Gao、Tianyi Zhang、Haichun Liu、Yanmin Zhang、Shuai Lu、Tao Lu、Yadong Chen、Hongmei Li

  DOI：10.1016/j.ejmech.2020.112517

  日期：2020.10

  Aberrant activation of p21-activated kinase 1 (PAK1) is associated with tumour progression, and PAK1 has been recognized as a promising target for anticancer drug discovery. However, the development of potent PAK1 inhibitors with satisfactory kinase selectivity and favourable physicochemical properties remains a daunting challenge. Herein, we identified the 1H-indazole-3-carboxamide derivatives as potential PAK1 inhibitors using a fragment-based screening approach. The representative compound 301 exhibited excellent enzyme inhibition (PAK1 IC50 = 9.8 nM) and high PAK1 selectivity toward a panel of 29 kinases. The Structure-activity relationship (SAR) analysis showed that substituting of an appropriate hydrophobic ring in the deep back pocket and introducing a hydrophilic group in the bulk solvent region were critical for PAK1 inhibitory activity and selectivity. Additionally, the hERG channel activity of 301 demonstrated its low risk of hERG toxicity. Furthermore, it significantly suppressed the migration and invasion of MDA-MB-231 cells by downregulating Snail expression without affecting the tumour growth. These results provide a new type of chemical scaffolds targeting PAK1 and suggested that 1H-indazole-3-carboxamide derivatives may serve as lead compounds for the development of potential and selective PAK1 inhibitors. (C) 2020 Elsevier Masson SAS. All rights reserved.