β-<<(phenylmethoxy)carbonyl>amino>-α-oxobenzenebutanoic acid ethyl ester | 121253-57-4

• 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: β-<<(phenylmethoxy)carbonyl>amino>-α-oxobenzenebutanoic acid ethyl ester
• 英文别名: 3-Benzyloxycarbonylamino-2-oxo-4-phenyl-butyric acid ethyl ester；ethyl (3S)-2-oxo-4-phenyl-3-(phenylmethoxycarbonylamino)butanoate
• CAS: 121253-57-4
• 化学式: C₂₀H₂₁NO₅
• 分子量: 355.39
• InChiKey: GOKJSEZDCPHHHR-KRWDZBQOSA-N

物化性质

• 沸点：
  533.3±50.0 °C(Predicted)
• 密度：
  1.203±0.06 g/cm3(Temp: 20 °C; Press: 760 Torr)(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.6
• 重原子数：
  26
• 可旋转键数：
  10
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.25
• 拓扑面积：
  81.7
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  β-<<(phenylmethoxy)carbonyl>amino>-α-oxobenzenebutanoic acid ethyl ester 在 lithium hydroxide 、 sodium tetrahydroborate 作用下， 以 甲醇 、 水 为溶剂， 反应 0.83h， 生成 (2R,3S)-3-benzyloxycarbonylamino-2-hydroxy-4-phenylbutanoic acid
  参考文献：
  名称：

  Selectivity in the Inhibition of HIV and FIV Protease: Inhibitory and Mechanistic Studies of Pyrrolidine-Containing .alpha.-Keto Amide and Hydroxyethylamine Core Structures

  摘要：

  This paper describes the development of new pyrrolidine-containing alpha-keto amide and hydroxyethylamine core structures as mechanism based inhibitors of the HIV and FIV proteases. It was found that the alpha-keto amide core structure 2 is approximately 300-fold better than the corresponding hydroxyethylamine isosteric structure and 1300-fold better than the corresponding phosphinic acid derivative as an inhibitor of the HIV protease. The alpha-keto amide is however not hydrated until it is bound to the HIV protease as indicated by the NMR study and the X-ray structural analysis. Further analysis of the inhibition activities of hydroxyethylamine isosteres containing modified pyrrolidine derivatives revealed that a cis-methoxy group at C-4 of the pyrrolidine would improve the binding 5-and 25-fold for the trans-isomer. When this strategy was applied to the alpha-keto amide isostere, a cis-benzyl ether at C-4 was found to enhance binding 3-fold. Of the core structures prepared as inhibitors of the HIV protease, none show significant inhibitory activity against the mechanistically identical FIV protease, and additional complementary groups are needed to improve inhibition.

  DOI：

  10.1021/ja00153a008
• 作为产物：
  描述：

  苄基(S)-1-(N-甲氧基-N-甲基氨基甲酰基)-2-苯乙基氨基甲酸酯 在 吡啶 、 二甲基硫 、 氧气 、 臭氧 作用下， 反应 0.05h， 生成 β-<<(phenylmethoxy)carbonyl>amino>-α-oxobenzenebutanoic acid ethyl ester
  参考文献：
  名称：

  An efficient synthesis of novel .alpha.-diketone and .alpha.-keto ester derivatives of N-protected amino acids and peptides

  摘要：

  DOI：

  10.1021/jo00277a031

文献信息

• HIV protease inhibitors
  申请人：Wong Chi-Huey

  公开号：US06900238B1

  公开（公告）日：2005-05-31

  Combinatorial libraries of HIV and FIV protease inhibitors are characterized by α-keto amide or hydroxyethylamine core structures flanked by on one side by substituted pyrrolidines, piperidines, or azasugars and on the other side by phenylalanine, tyrosine, or substituted tyrosines. The libraries are synthesized via a one step coupling reaction. Highly efficacious drug candidates are identified by screening the libraries for binding and inhibitory activity against both HIV and FIV protease. Drug candidates displaying clinically useful activity against both HIV and FIV protease are identified as being potentially resistive against a loss of inhibitory activity due to development of resistant strains of HIV.

  HIV和FIV蛋白酶抑制剂的组合库以α-酮酰胺或羟乙基胺核心结构为特征，一侧为取代吡咯烷、哌啶或氮代糖，另一侧为苯丙氨酸、酪氨酸或取代酪氨酸。这些库是通过一步偶联反应合成的。通过筛选这些库，识别出对HIV和FIV蛋白酶的结合和抑制活性高效的药物候选化合物。对HIV和FIV蛋白酶都显示出临床有用活性的药物候选化合物被确定为潜在对抗由于HIV耐药株的发展而导致的抑制活性丧失。
• An efficient synthesis of novel .alpha.-diketone and .alpha.-keto ester derivatives of N-protected amino acids and peptides
  作者：Michael R. Angelastro、Norton P. Peet、Philippe Bey

  DOI：10.1021/jo00277a031

  日期：1989.8
• ANGELASTRO, MICHAEL R.;PEET, NORTON P.;BEY, PHILIPPE, J. ORG. CHEM., 54,(1989) N6, C. 3913-3916
  作者：ANGELASTRO, MICHAEL R.、PEET, NORTON P.、BEY, PHILIPPE

  DOI：——

  日期：——
• PEET, N. P.;BURKHART, J. P., J. MED. CHEM., 33,(1990) N, C. 11-13
  作者：PEET, N. P.、BURKHART, J. P.

  DOI：——

  日期：——
• Selectivity in the Inhibition of HIV and FIV Protease: Inhibitory and Mechanistic Studies of Pyrrolidine-Containing .alpha.-Keto Amide and Hydroxyethylamine Core Structures
  作者：Deborah H. Slee、Karen L. Laslo、John H. Elder、Ian R. Ollmann、Alla Gustchina、Jukka Kervinen、Alexander Zdanov、Alexander Wlodawer、Chi-Huey Wong

  DOI：10.1021/ja00153a008

  日期：1995.12

  This paper describes the development of new pyrrolidine-containing alpha-keto amide and hydroxyethylamine core structures as mechanism based inhibitors of the HIV and FIV proteases. It was found that the alpha-keto amide core structure 2 is approximately 300-fold better than the corresponding hydroxyethylamine isosteric structure and 1300-fold better than the corresponding phosphinic acid derivative as an inhibitor of the HIV protease. The alpha-keto amide is however not hydrated until it is bound to the HIV protease as indicated by the NMR study and the X-ray structural analysis. Further analysis of the inhibition activities of hydroxyethylamine isosteres containing modified pyrrolidine derivatives revealed that a cis-methoxy group at C-4 of the pyrrolidine would improve the binding 5-and 25-fold for the trans-isomer. When this strategy was applied to the alpha-keto amide isostere, a cis-benzyl ether at C-4 was found to enhance binding 3-fold. Of the core structures prepared as inhibitors of the HIV protease, none show significant inhibitory activity against the mechanistically identical FIV protease, and additional complementary groups are needed to improve inhibition.