methyl 5-[(2,2-dimethylpropanoyl)oxy]-6-hydroxy-2-{3-[(phenoxycarbonyl)amino]-2-thienyl}pyrimidine-4-carboxylate | 923949-36-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 英文名称: methyl 5-[(2,2-dimethylpropanoyl)oxy]-6-hydroxy-2-{3-[(phenoxycarbonyl)amino]-2-thienyl}pyrimidine-4-carboxylate
• 英文别名: methyl 5-(2,2-dimethylpropanoyloxy)-6-oxo-2-[3-(phenoxycarbonylamino)thiophen-2-yl]-1H-pyrimidine-4-carboxylate
• CAS: 923949-36-4
• 化学式: C₂₂H₂₁N₃O₇S
• 分子量: 471.491
• InChiKey: YBVJTEJABOPDNC-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.5
• 重原子数：
  33
• 可旋转键数：
  9
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.23
• 拓扑面积：
  161
• 氢给体数：
  2
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  methyl 5-[(2,2-dimethylpropanoyl)oxy]-6-hydroxy-2-{3-[(phenoxycarbonyl)amino]-2-thienyl}pyrimidine-4-carboxylate 在 sodium hydroxide 作用下， 以 甲醇 、 二甲基亚砜 为溶剂， 反应 4.0h， 生成 2-[3-(3-Benzo[b]thiophen-3-ylmethyl-ureido)-thiophen-2-yl]-5,6-dihydroxy-pyrimidine-4-carboxylic acid
  参考文献：
  名称：

  2-(2-Thienyl)-5,6-dihydroxy-4-carboxypyrimidines as Inhibitors of the Hepatitis C Virus NS5B Polymerase:  Discovery, SAR, Modeling, and Mutagenesis

  摘要：

  Infections caused by hepatitis C virus (HCV) are a significant world health problem for which novel therapies are in urgent demand. The polymerase of HCV is responsible for the replication of viral RNA. We recently disclosed dihydroxypyrimidine carboxylates 2 as novel, reversible inhibitors of the HCV NS5B polymerase. This series was further developed into 5,6-dihydroxy-2-(2-thienyl)pyrimidine-4-carboxylic acids such as 34 (EC50 9.3 mu M), which now show activity in the cell-based HCV replication assay. The structure-activity relationship of these inhibitors is discussed in the context of their physicochemical properties and of the polymerase crystal structure. We also report the results of mutagenesis experiments which support the proposed binding model, which involves pyrophosphate-like chelation of the active site Mg ions.

  DOI：

  10.1021/jm051064t
• 作为产物：
  描述：

  methyl 5,6-dihydroxy-2-(3-nitro-2-thienyl)pyrimidine-4-carboxylate 在 palladium on activated charcoal 吡啶 、 4-二甲氨基吡啶 、 氢气 作用下， 以 四氢呋喃 、 甲醇 、 乙酸乙酯 为溶剂， 20.0 ℃ 、101.33 kPa 条件下， 反应 7.0h， 生成 methyl 5-[(2,2-dimethylpropanoyl)oxy]-6-hydroxy-2-{3-[(phenoxycarbonyl)amino]-2-thienyl}pyrimidine-4-carboxylate
  参考文献：
  名称：

  2-(2-Thienyl)-5,6-dihydroxy-4-carboxypyrimidines as Inhibitors of the Hepatitis C Virus NS5B Polymerase:  Discovery, SAR, Modeling, and Mutagenesis

  摘要：

  Infections caused by hepatitis C virus (HCV) are a significant world health problem for which novel therapies are in urgent demand. The polymerase of HCV is responsible for the replication of viral RNA. We recently disclosed dihydroxypyrimidine carboxylates 2 as novel, reversible inhibitors of the HCV NS5B polymerase. This series was further developed into 5,6-dihydroxy-2-(2-thienyl)pyrimidine-4-carboxylic acids such as 34 (EC50 9.3 mu M), which now show activity in the cell-based HCV replication assay. The structure-activity relationship of these inhibitors is discussed in the context of their physicochemical properties and of the polymerase crystal structure. We also report the results of mutagenesis experiments which support the proposed binding model, which involves pyrophosphate-like chelation of the active site Mg ions.

  DOI：

  10.1021/jm051064t

文献信息

• 2-(2-Thienyl)-5,6-dihydroxy-4-carboxypyrimidines as Inhibitors of the Hepatitis C Virus NS5B Polymerase:  Discovery, SAR, Modeling, and Mutagenesis
  作者：Uwe Koch、Barbara Attenni、Savina Malancona、Stefania Colarusso、Immacolata Conte、Marcello Di Filippo、Steven Harper、Barbara Pacini、Claudia Giomini、Steven Thomas、Ilario Incitti、Licia Tomei、Raffaele De Francesco、Sergio Altamura、Victor G. Matassa、Frank Narjes

  DOI：10.1021/jm051064t

  日期：2006.3.1

  Infections caused by hepatitis C virus (HCV) are a significant world health problem for which novel therapies are in urgent demand. The polymerase of HCV is responsible for the replication of viral RNA. We recently disclosed dihydroxypyrimidine carboxylates 2 as novel, reversible inhibitors of the HCV NS5B polymerase. This series was further developed into 5,6-dihydroxy-2-(2-thienyl)pyrimidine-4-carboxylic acids such as 34 (EC50 9.3 mu M), which now show activity in the cell-based HCV replication assay. The structure-activity relationship of these inhibitors is discussed in the context of their physicochemical properties and of the polymerase crystal structure. We also report the results of mutagenesis experiments which support the proposed binding model, which involves pyrophosphate-like chelation of the active site Mg ions.