N-<1-phenyl-2(S)-<(benzyloxycarbonyl)amino>-3(R)-hydroxybutan>-4-L-prolyl-tert-butyl amide | 128018-20-2

• 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: N-<1-phenyl-2(S)-<(benzyloxycarbonyl)amino>-3(R)-hydroxybutan>-4-L-prolyl-tert-butyl amide
• 英文别名: N-[1-phenyl-2(S)-(benzyloxycarbonyl)amino]-3(R)-hydroxybutan-4-L-prolyl-tert-butyl amide；benzyl N-[(1S,2R)-1-benzyl-3-[(2S)-2-(tert-butylcarbamoyl)pyrrolidin-1-yl]-2-hydroxy-propyl]carbamate；benzyl N-[(2S,3R)-4-[(2S)-2-(tert-butylcarbamoyl)pyrrolidin-1-yl]-3-hydroxy-1-phenylbutan-2-yl]carbamate
• CAS: 128018-20-2
• 化学式: C₂₇H₃₇N₃O₄
• 分子量: 467.608
• InChiKey: BXBSQDDEVVPEES-KMDXXIMOSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.7
• 重原子数：
  34
• 可旋转键数：
  11
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.48
• 拓扑面积：
  90.9
• 氢给体数：
  3
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  N-<1-phenyl-2(S)-<(benzyloxycarbonyl)amino>-3(R)-hydroxybutan>-4-L-prolyl-tert-butyl amide 在 palladium on activated charcoal 氢气 作用下， 以 乙酸乙酯 为溶剂， 生成 (S)-1-((2R,3S)-3-Amino-2-hydroxy-4-phenyl-butyl)-pyrrolidine-2-carboxylic acid tert-butylamide
  参考文献：
  名称：

  Development of a New Type of Protease Inhibitors, Efficacious against FIV and HIV Variants

  摘要：

  Based on the structural analysis of FIV protease and drug-resistant HIV proteases and molecular modeling, a new type of inhibitors with a small P3 residue has been developed. These inhibitors are effective against HIV and its drug-resistant mutants, as well as SIV and FIV. Modification of existing HIV protease inhibitors by reducing the size of the P3 residue has the same effect. This finding provides a new strategy for the development of HIV protease inhibitors effective against the wild-type and drug-resistant mutants. It further supports the use of FIV protease as a useful model for drug-resistant HIV proteases, which often have a more constricted binding region for the P3 group or the combined P3 and P1 groups.

  DOI：

  10.1021/ja982893p
• 作为产物：
  描述：

  Z-Phe-O-COO-isoBu 在 盐酸 、 sodium tetrahydroborate 、 sodium methylate 、 三乙胺 作用下， 以 甲醇 、 乙醇 为溶剂， 生成 N-<1-phenyl-2(S)-<(benzyloxycarbonyl)amino>-3(R)-hydroxybutan>-4-L-prolyl-tert-butyl amide
  参考文献：
  名称：

  Development of a New Type of Protease Inhibitors, Efficacious against FIV and HIV Variants

  摘要：

  Based on the structural analysis of FIV protease and drug-resistant HIV proteases and molecular modeling, a new type of inhibitors with a small P3 residue has been developed. These inhibitors are effective against HIV and its drug-resistant mutants, as well as SIV and FIV. Modification of existing HIV protease inhibitors by reducing the size of the P3 residue has the same effect. This finding provides a new strategy for the development of HIV protease inhibitors effective against the wild-type and drug-resistant mutants. It further supports the use of FIV protease as a useful model for drug-resistant HIV proteases, which often have a more constricted binding region for the P3 group or the combined P3 and P1 groups.

  DOI：

  10.1021/ja982893p

文献信息

• 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.
• Development of a New Type of Protease Inhibitors, Efficacious against FIV and HIV Variants
  作者：Taekyu Lee、Van-Duc Le、Dongyeol Lim、Ying-Chuan Lin、Garrett M. Morris、Andrew L. Wong、Arthur J. Olson、John H. Elder、Chi-Huey Wong

  DOI：10.1021/ja982893p

  日期：1999.2.1

  Based on the structural analysis of FIV protease and drug-resistant HIV proteases and molecular modeling, a new type of inhibitors with a small P3 residue has been developed. These inhibitors are effective against HIV and its drug-resistant mutants, as well as SIV and FIV. Modification of existing HIV protease inhibitors by reducing the size of the P3 residue has the same effect. This finding provides a new strategy for the development of HIV protease inhibitors effective against the wild-type and drug-resistant mutants. It further supports the use of FIV protease as a useful model for drug-resistant HIV proteases, which often have a more constricted binding region for the P3 group or the combined P3 and P1 groups.
• An unusual functional group interaction and its potential to reproduce steric and electrostatic features of the transition states of peptidolysis
  作者：Arnaud Gautier、Delphine Pitrat、Jens Hasserodt

  DOI：10.1016/j.bmc.2006.01.031

  日期：2006.6

  The donor-acceptor interaction between a tertiary amine and an aldehyde, first observed among a select class of alkaloids, was deliberately established in a peptidomimetic (1a-c) to mimic features of the two principal transition states of peptide hydrolysis. Compounds la-c show preferential adoption in methanol and water of a 'folded' conformation displaying the interaction. Proportions of the folded form in MeOH range from 45% to 70% and can reach 84% in buffer. Significantly, three tendencies for the folded/unfolded equilibrium are observed: increasing solubility and polarity of the medium and decreasing temperature results in a higher extent of folding. In the absence of any parameter set available for this weak bond, no modeling studies were conducted to aid in the design of 1a-c. The successful straightforward synthesis of 1 and its folding and inhibition results with HIV-1 peptidase using FRET technology encourage studies to further preorganize candidate molecules and to screen the structure space by modeling and parallel combinatorial chemistry. (c) 2006 Elsevier Ltd. All rights reserved.