Methyl 2-(1-cyanoethylamino)-2-phenylacetate | 1247083-62-0

• 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: Methyl 2-(1-cyanoethylamino)-2-phenylacetate
• CAS: 1247083-62-0
• 化学式: C₁₂H₁₄N₂O₂
• 分子量: 218.255
• InChiKey: QYKGWNBDYAKCFA-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.6
• 重原子数：
  16
• 可旋转键数：
  5
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  62.1
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  Methyl 2-(1-cyanoethylamino)-2-phenylacetate 在 盐酸 、 二氯乙酸 、 水 、 palladium diacetate 、 potassium carbonate 、 caesium carbonate 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 N,N-二异丙基乙胺 、 4,5-双二苯基膦-9,9-二甲基氧杂蒽 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 作用下， 以 乙二醇二甲醚 、 乙醚 、 二氯甲烷 、 二甲基亚砜 、 乙腈 为溶剂， 反应 4.82h， 生成 3-(2-(3-(3-(tert-butyl)ureido)-5-chloro-6-methyl-2-oxopyrazin-1(2H)-yl)-2-phenylacetamido)-4-cyclobutyl-2-oxobutanamide
  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.