2-(2-(3-(3-(tert-butyl)ureido)-5-chloro-2-oxo-6-(3-(pyridin-3-yl)phenyl)pyrazin-1(2H)-yl)acetamido)-N-((4-(trifluoromethyl)phenyl)sulfonyl)benzamide | 1428533-73-6

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 2-(2-(3-(3-(tert-butyl)ureido)-5-chloro-2-oxo-6-(3-(pyridin-3-yl)phenyl)pyrazin-1(2H)-yl)acetamido)-N-((4-(trifluoromethyl)phenyl)sulfonyl)benzamide
• 英文别名: 2-[[2-[3-(tert-butylcarbamoylamino)-5-chloro-2-oxo-6-[3-(3-pyridyl)phenyl]pyrazin-1-yl]acetyl]amino]-N-[4-(trifluoromethyl)phenyl]sulfonyl-benzamide；2-[[2-[3-(tert-butylcarbamoylamino)-5-chloro-2-oxo-6-(3-pyridin-3-ylphenyl)pyrazin-1-yl]acetyl]amino]-N-[4-(trifluoromethyl)phenyl]sulfonylbenzamide
• CAS: 1428533-73-6
• 化学式: C₃₆H₃₁ClF₃N₇O₆S
• 分子量: 782.2
• InChiKey: ALAHZYZPFZASAY-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.7
• 重原子数：
  54
• 可旋转键数：
  10
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.17
• 拓扑面积：
  187
• 氢给体数：
  4
• 氢受体数：
  11

反应信息

• 作为产物：
  描述：

  benzyl 2-(6-(3-bromophenyl)-3-(3-(tert-butyl)ureido)-5-chloro-2-oxopyrazin-1(2H)-yl)acetate 在 吡啶 、 bis-triphenylphosphine-palladium(II) chloride 、 水 、 sodium carbonate 、 potassium carbonate 、 三氯氧磷 作用下， 以 乙二醇二甲醚 、 乙醇 、 水 、 乙腈 为溶剂， 反应 1.0h， 生成 2-(2-(3-(3-(tert-butyl)ureido)-5-chloro-2-oxo-6-(3-(pyridin-3-yl)phenyl)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

文献信息

• Achiral Pyrazinone-Based Inhibitors of the Hepatitis C Virus NS3 Protease and Drug-Resistant Variants with Elongated Substituents Directed Toward the S2 Pocket
  作者：Johan Gising、Anna Karin Belfrage、Hiba Alogheli、Angelica Ehrenberg、Eva Åkerblom、Richard Svensson、Per Artursson、Anders Karlén、U. Helena Danielson、Mats Larhed、Anja Sandström

  DOI：10.1021/jm301887f

  日期：2014.3.13

  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.