benzyl 2-(3,5-dichloro-6-(2-cyclohexylethyl)-2-oxopyrazin-1(2H)-yl)acetate | 1428533-28-1

• 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-6-(2-cyclohexylethyl)-2-oxopyrazin-1(2H)-yl)acetate
• CAS: 1428533-28-1
• 化学式: C₂₁H₂₄Cl₂N₂O₃
• 分子量: 423.339
• InChiKey: JKBIKULSOSHBLI-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.81
• 重原子数：
  28.0
• 可旋转键数：
  7.0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.48
• 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-6-(2-cyclohexylethyl)-2-oxopyrazin-1(2H)-yl)acetate 在 水 、 palladium diacetate 、 potassium carbonate 、 caesium carbonate 、 4,5-双二苯基膦-9,9-二甲基氧杂蒽 作用下， 以 乙二醇二甲醚 、 乙腈 为溶剂， 反应 0.5h， 生成
  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：

  甘氨酸苄酯盐酸盐 在 盐酸 、 N,N-二异丙基乙胺 作用下， 以 乙二醇二甲醚 、 乙醚 为溶剂， 反应 0.69h， 生成 benzyl 2-(3,5-dichloro-6-(2-cyclohexylethyl)-2-oxopyrazin-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

文献信息

• Pan-NS3 protease inhibitors of hepatitis C virus based on an R3-elongated pyrazinone scaffold
  作者：Anna Karin Belfrage、Eldar Abdurakhmanov、Eva Åkerblom、Peter Brandt、Hiba Alogheli、Johan Neyts、U. Helena Danielson、Anja Sandström

  DOI：10.1016/j.ejmech.2018.02.032

  日期：2018.3

  HCV NS3 protease inhibitors and show that elongated R3 urea substituents were associated with increased inhibitory potencies over several NS3 protein variants. The inhibitors are believed to rely on β-sheet mimicking hydrogen bonds which are similar over different genotypes and current drug resistant variants and correspond to the β-sheet interactions of the natural peptide substrate. Inhibitor 36, for

  在本文中，我们介绍了基于2（1 H）-吡嗪酮的HCV NS3蛋白酶抑制剂的设计和合成，并显示了延长的R 3尿素取代基与几种 蛋白变体的抑制能力增强相关。据信抑制剂依赖于模拟氢键的β-折叠，该氢键在不同的基因型和当前的抗药性变体上是相似的，并且对应于天然肽底物的β-折叠相互作用。例如，具有包括环状酰亚胺的尿素取代基的抑制剂36对基因型1a，野生型（K i  = 30 nM）和R155K（K i  = 2 nM）和基因型3a（Ki  = 5 nM）。