(3S,4S)-4-amino-1-(2-ethylbutanoyl)pyrrolidine-3-carboxylic acid

• 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: (3S,4S)-4-amino-1-(2-ethylbutanoyl)pyrrolidine-3-carboxylic acid
• 化学式: C₁₁H₂₀N₂O₃
• 分子量: 228.291
• InChiKey: QUNRCMDAJDSMHO-DTWKUNHWSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -1.8
• 重原子数：
  16
• 可旋转键数：
  4
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.82
• 拓扑面积：
  83.6
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  di-tert-butyl 4-(benzylamino)-1H-pyrrole-1,3(2H,5H)-dicarboxylate 在 10 percent Pd/C sodium tetrahydroborate 、 水 、 氢气 、 溶剂黄146 、 三氟乙酸 作用下， 以 1,4-二氧六环 、 甲醇 、 二氯甲烷 为溶剂， 反应 12.5h， 生成 (3S,4S)-4-amino-1-(2-ethylbutanoyl)pyrrolidine-3-carboxylic acid
  参考文献：
  名称：

  Design, Synthesis, and Structural Analysis of Influenza Neuraminidase Inhibitors Containing Pyrrolidine Cores

  摘要：

  The discovery of (+/-)-(2S,3R,4R)-2-(trifluoroacetamido)methyl-3-amino-1-(N ' -ethyl-N ' -isopropylcarbamyl)pyrrolidine-4-earboxylic acid (A-192558, 20e) as a potent inhibitor of influenza neuraminidase (NA) is described. Efficient syntheses of two core structures, cis-3-(allyloxy-carbonyl)amino-1-(9 ' -fluorenylmethoxycarbonyl)pyrrolidine-4-carboxylic acid (7) and tert-butyl (+/-)(2S, 3R,4R)-2-aminomethyl-3-bis(tert-butyloxycarbonyl) amino-1-(N ' -ethyl-N ' -isopropylcarbamyl)pyrrolidine-4-carboxylate (18b), were developed. Starting with these core structures and using available structural information of the NA active site as the guide, analogues were synthesized in both the tri- and tetrasubstituted pyrrolidine series by means of high-throughput parallel synthesis in solid or solution phase for expeditious SAR. These studies accelerated the identification of(+/-)-(2S,3R,4R)-2-(trifluoroacetamido)methyl-3-amino-1-(N-ethyl-N-isopropylcarbamyl)pyrrolidine-4-carboxylate (20e, A-192558) as the most potent NA inhibitor in this series (IC50 = 0.2 muM against NA A and 8 muM against NA B). The X-ray crystallographic structure of A-192558 bound to NA revealed the predicted interaction of the carboxylic group with the positively charged pocket (Arg118, Arg292, Arg371) and interaction of the trifluoro-acetamino residue with the hydrophobic pocket (Ile222, Trp178) of the enzyme active site. Surprisingly, the ethyl and isopropyl groups of the urea functionality induced a conformational change of Glu276, turning the Glu276/Glu277 hydrophilic pocket, which normally accommodates the triglycerol side chain of substrate sialic acid, into an induced hydrophobic pocket.

  DOI：

  10.1021/jm000468c

文献信息

• Design, Synthesis, and Structural Analysis of Influenza Neuraminidase Inhibitors Containing Pyrrolidine Cores
  作者：Gary T. Wang、Yuanwei Chen、Sheldon Wang、Robert Gentles、Thomas Sowin、Warren Kati、Steve Muchmore、Vincent Giranda、Kent Stewart、Hing Sham、Dale Kempf、W. Graeme Laver

  DOI：10.1021/jm000468c

  日期：2001.4.1

  The discovery of (+/-)-(2S,3R,4R)-2-(trifluoroacetamido)methyl-3-amino-1-(N ' -ethyl-N ' -isopropylcarbamyl)pyrrolidine-4-earboxylic acid (A-192558, 20e) as a potent inhibitor of influenza neuraminidase (NA) is described. Efficient syntheses of two core structures, cis-3-(allyloxy-carbonyl)amino-1-(9 ' -fluorenylmethoxycarbonyl)pyrrolidine-4-carboxylic acid (7) and tert-butyl (+/-)(2S, 3R,4R)-2-aminomethyl-3-bis(tert-butyloxycarbonyl) amino-1-(N ' -ethyl-N ' -isopropylcarbamyl)pyrrolidine-4-carboxylate (18b), were developed. Starting with these core structures and using available structural information of the NA active site as the guide, analogues were synthesized in both the tri- and tetrasubstituted pyrrolidine series by means of high-throughput parallel synthesis in solid or solution phase for expeditious SAR. These studies accelerated the identification of(+/-)-(2S,3R,4R)-2-(trifluoroacetamido)methyl-3-amino-1-(N-ethyl-N-isopropylcarbamyl)pyrrolidine-4-carboxylate (20e, A-192558) as the most potent NA inhibitor in this series (IC50 = 0.2 muM against NA A and 8 muM against NA B). The X-ray crystallographic structure of A-192558 bound to NA revealed the predicted interaction of the carboxylic group with the positively charged pocket (Arg118, Arg292, Arg371) and interaction of the trifluoro-acetamino residue with the hydrophobic pocket (Ile222, Trp178) of the enzyme active site. Surprisingly, the ethyl and isopropyl groups of the urea functionality induced a conformational change of Glu276, turning the Glu276/Glu277 hydrophilic pocket, which normally accommodates the triglycerol side chain of substrate sialic acid, into an induced hydrophobic pocket.