benzyl 2-(3,5-dichloro-2-oxo-6-(3-phenylpropyl)pyrazin-1(2H)-yl)acetate | 1428533-23-6

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: benzyl 2-(3,5-dichloro-2-oxo-6-(3-phenylpropyl)pyrazin-1(2H)-yl)acetate
• CAS: 1428533-23-6
• 化学式: C₂₂H₂₀Cl₂N₂O₃
• 分子量: 431.318
• InChiKey: WWSVGWTVYHZEOZ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.47
• 重原子数：
  29.0
• 可旋转键数：
  8.0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.23
• 拓扑面积：
  61.19
• 氢给体数：
  0.0
• 氢受体数：
  5.0

反应信息

• 作为反应物：
  描述：

  benzyl 2-(3,5-dichloro-2-oxo-6-(3-phenylpropyl)pyrazin-1(2H)-yl)acetate 在 吡啶 、 水 、 palladium diacetate 、 potassium carbonate 、 caesium carbonate 、 4,5-双二苯基膦-9,9-二甲基氧杂蒽 、 三氯氧磷 作用下， 以 乙二醇二甲醚 、 乙腈 为溶剂， 反应 3.5h， 生成 2-(2-(3-(3-(tert-butyl)ureido)-5-chloro-2-oxo-6-(3-phenylpropyl)pyrazin-1(2H)-yl)acetamido)-N-(((4-trifluoromethyl)phenyl)sulfonyl)benzamide
  参考文献：
  名称：

  Achiral Pyrazinone-Based Inhibitors of the Hepatitis C Virus NS3 Protease and Drug-Resistant Variants with Elongated Substituents Directed Toward the S2 Pocket

  摘要：

  Herein we describe the design, synthesis, inhibitory potency, and pharmacokinetic properties of a novel class of achiral peptidomimetic HCV NS3 protease inhibitors. The compounds are based on a dipeptidomimetic pyrazinone glycine P3P2 building block in combination with an aromatic acyl sulfonamide in the P1P1' position. Structure-activity relationship data and molecular modeling support occupancy of the S2 pocket from elongated R-6 substituents on the 2(1H)-pyrazinone core and several inhibitors with improved inhibitory potency down to K-i = 0.11 mu M were identified. A major goal with the design was to produce inhibitors structurally dissimilar to the di- and tripeptide-based HCV protease inhibitors in advanced stages of development for which cross-resistance might be an issue. Therefore, the retained and improved inhibitory potency against the drug-resistant variants A156T, D168V, and R155K further strengthen the potential of this class of inhibitors. A number of the inhibitors were tested in in vitro preclinical profiling assays to evaluate their apparent pharmacokinetic properties. The various R6 substituents were found to have a major influence on solubility, metabolic stability, and cell permeability.

  DOI：

  10.1021/jm301887f
• 作为产物：
  描述：

  4-苯基丁醛 在 盐酸 、 N,N-二异丙基乙胺 作用下， 以 乙醚 、 二氯甲烷 、 二甲基亚砜 为溶剂， 反应 1.1h， 生成 benzyl 2-(3,5-dichloro-2-oxo-6-(3-phenylpropyl)pyrazin-1(2H)-yl)acetate
  参考文献：
  名称：

  Achiral Pyrazinone-Based Inhibitors of the Hepatitis C Virus NS3 Protease and Drug-Resistant Variants with Elongated Substituents Directed Toward the S2 Pocket

  摘要：

  Herein we describe the design, synthesis, inhibitory potency, and pharmacokinetic properties of a novel class of achiral peptidomimetic HCV NS3 protease inhibitors. The compounds are based on a dipeptidomimetic pyrazinone glycine P3P2 building block in combination with an aromatic acyl sulfonamide in the P1P1' position. Structure-activity relationship data and molecular modeling support occupancy of the S2 pocket from elongated R-6 substituents on the 2(1H)-pyrazinone core and several inhibitors with improved inhibitory potency down to K-i = 0.11 mu M were identified. A major goal with the design was to produce inhibitors structurally dissimilar to the di- and tripeptide-based HCV protease inhibitors in advanced stages of development for which cross-resistance might be an issue. Therefore, the retained and improved inhibitory potency against the drug-resistant variants A156T, D168V, and R155K further strengthen the potential of this class of inhibitors. A number of the inhibitors were tested in in vitro preclinical profiling assays to evaluate their apparent pharmacokinetic properties. The various R6 substituents were found to have a major influence on solubility, metabolic stability, and cell permeability.

  DOI：

  10.1021/jm301887f