ethyl 5-amino-1-(2,6-difluorophenyl)-1H-pyrazole-4-carboxylate | 1186491-29-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: ethyl 5-amino-1-(2,6-difluorophenyl)-1H-pyrazole-4-carboxylate
• 英文别名: ethyl 5-amino-1-(2,6-difluorophenyl)pyrazole-4-carboxylate
• CAS: 1186491-29-1
• 化学式: C₁₂H₁₁F₂N₃O₂
• 分子量: 267.235
• InChiKey: FQHHCSGQEVQTGD-UHFFFAOYSA-N

物化性质

• 沸点：
  381.6±42.0 °C(Predicted)
• 密度：
  1.40±0.1 g/cm3(Temp: 20 °C; Press: 760 Torr)(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.91
• 重原子数：
  19.0
• 可旋转键数：
  3.0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.17
• 拓扑面积：
  70.14
• 氢给体数：
  1.0
• 氢受体数：
  5.0

反应信息

• 作为反应物：
  描述：

  ethyl 5-amino-1-(2,6-difluorophenyl)-1H-pyrazole-4-carboxylate 在 碘 、 亚硝酸异戊酯 作用下， 以 氯仿 为溶剂， 生成 C₁₂H₉F₂IN₂O₂
  参考文献：
  名称：

  Part 2: Structure–activity relationship (SAR) investigations of fused pyrazoles as potent, selective and orally available inhibitors of p38α mitogen-activated protein kinase

  摘要：

  A novel class of pyrazolopyridazine p38 alpha mitogen-activated protein kinase (MAPK) inhibitors is disclosed. A structure activity relationship (SAR) investigation was conducted driven by the ability of these compounds to inhibit the p38a enzyme, the secretion of TNF alpha in a LPS-challenged THP1 cell line and TNF alpha-induced production of IL-8 in the presence of 50% human whole blood (hWB). This study resulted in the discovery of several inhibitors with IC50 values in the single-digit nanomolar range in hWB. Further investigation of the pharmacokinetic profiles of these lead compounds led to the identification of three potent and orally bioavailable p38 alpha inhibitors 2h, 2m, and 13h. Inhibitor 2m was found to be highly selective for p38 alpha/beta over a panel of 402 other kinases in Ambit screening, and was highly efficacious in vivo in the inhibition of TNF alpha production in LPS-stimulated Lewis rats with an ED50 of ca. 0.08 mg/kg. (C) 2010 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2010.01.059
• 作为产物：
  描述：

  6-(三氟甲基)烟腈 、 2-氰基-3-乙氧基丙烯酸乙酯 在 三乙胺 作用下， 以 乙醇 为溶剂， 生成 ethyl 5-amino-1-(2,6-difluorophenyl)-1H-pyrazole-4-carboxylate
  参考文献：
  名称：

  Part 1: Structure–Activity Relationship (SAR) investigations of fused pyrazoles as potent, selective and orally available inhibitors of p38α mitogen-activated protein kinase

  摘要：

  A novel class of fused pyrazole-derived inhibitors of p38 alpha mitogen-activated protein kinase (MAPK) is disclosed. These inhibitors were evaluated for their ability to inhibit the p38a enzyme, the secretion of TNF alpha in a LPS-challenged THP1 cell line and TNF alpha-induced production of IL-8 in 50% human whole blood. This series was optimized through a SAR investigation to provide inhibitors with IC50 values in the low single-digit nanomolar range in whole blood. Further investigation of their pharmacokinetic profiles led to the identification of two potent and orally bioavailable p38 inhibitors 10m and 10q. Inhibitor 10m was found to be efficacious in vivo in the inhibition of TNFa production in LPS-stimulated Lewis rats with an ED50 of 0.1 mg/kg while 10q was found to have an ED50 of 0.05-0.07 mg/kg. (C) 2009 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2009.06.058

文献信息

• Part 1: Structure–Activity Relationship (SAR) investigations of fused pyrazoles as potent, selective and orally available inhibitors of p38α mitogen-activated protein kinase
  作者：Ryan P. Wurz、Liping H. Pettus、Shimin Xu、Bradley Henkle、Lisa Sherman、Matthew Plant、Kent Miner、Helen McBride、Lu Min Wong、Christiaan J.M. Saris、Matthew R. Lee、Samer Chmait、Christopher Mohr、Faye Hsieh、Andrew S. Tasker

  DOI：10.1016/j.bmcl.2009.06.058

  日期：2009.8

  A novel class of fused pyrazole-derived inhibitors of p38 alpha mitogen-activated protein kinase (MAPK) is disclosed. These inhibitors were evaluated for their ability to inhibit the p38a enzyme, the secretion of TNF alpha in a LPS-challenged THP1 cell line and TNF alpha-induced production of IL-8 in 50% human whole blood. This series was optimized through a SAR investigation to provide inhibitors with IC50 values in the low single-digit nanomolar range in whole blood. Further investigation of their pharmacokinetic profiles led to the identification of two potent and orally bioavailable p38 inhibitors 10m and 10q. Inhibitor 10m was found to be efficacious in vivo in the inhibition of TNFa production in LPS-stimulated Lewis rats with an ED50 of 0.1 mg/kg while 10q was found to have an ED50 of 0.05-0.07 mg/kg. (C) 2009 Elsevier Ltd. All rights reserved.
• Part 2: Structure–activity relationship (SAR) investigations of fused pyrazoles as potent, selective and orally available inhibitors of p38α mitogen-activated protein kinase
  作者：Ryan P. Wurz、Liping H. Pettus、Bradley Henkle、Lisa Sherman、Matthew Plant、Kent Miner、Helen J. McBride、Lu Min Wong、Christiaan J.M. Saris、Matthew R. Lee、Samer Chmait、Christopher Mohr、Faye Hsieh、Andrew S. Tasker

  DOI：10.1016/j.bmcl.2010.01.059

  日期：2010.3

  A novel class of pyrazolopyridazine p38 alpha mitogen-activated protein kinase (MAPK) inhibitors is disclosed. A structure activity relationship (SAR) investigation was conducted driven by the ability of these compounds to inhibit the p38a enzyme, the secretion of TNF alpha in a LPS-challenged THP1 cell line and TNF alpha-induced production of IL-8 in the presence of 50% human whole blood (hWB). This study resulted in the discovery of several inhibitors with IC50 values in the single-digit nanomolar range in hWB. Further investigation of the pharmacokinetic profiles of these lead compounds led to the identification of three potent and orally bioavailable p38 alpha inhibitors 2h, 2m, and 13h. Inhibitor 2m was found to be highly selective for p38 alpha/beta over a panel of 402 other kinases in Ambit screening, and was highly efficacious in vivo in the inhibition of TNF alpha production in LPS-stimulated Lewis rats with an ED50 of ca. 0.08 mg/kg. (C) 2010 Elsevier Ltd. All rights reserved.