(3S,4aS,8aS)-2-[(2R,3S)-3-((S)-2-Azido-2-(S)-tetrahydro-furan-3-yl-acetylamino)-2-hydroxy-4-phenyl-butyl]-decahydro-isoquinoline-3-carboxylic acid tert-butylamide | 150406-33-0

• 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: (3S,4aS,8aS)-2-[(2R,3S)-3-((S)-2-Azido-2-(S)-tetrahydro-furan-3-yl-acetylamino)-2-hydroxy-4-phenyl-butyl]-decahydro-isoquinoline-3-carboxylic acid tert-butylamide
• CAS: 150406-33-0
• 化学式: C₃₀H₄₆N₆O₄
• 分子量: 554.733
• InChiKey: NTTSFQXPTLFISV-RTYRAYMOSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.59
• 重原子数：
  40.0
• 可旋转键数：
  10.0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.73
• 拓扑面积：
  139.66
• 氢给体数：
  3.0
• 氢受体数：
  6.0

反应信息

• 作为反应物：
  描述：

  (3S,4aS,8aS)-2-[(2R,3S)-3-((S)-2-Azido-2-(S)-tetrahydro-furan-3-yl-acetylamino)-2-hydroxy-4-phenyl-butyl]-decahydro-isoquinoline-3-carboxylic acid tert-butylamide 在 palladium on activated charcoal 氢气 作用下， 以 四氢呋喃 、 甲醇 为溶剂， 反应 12.0h， 以0.12 g的产率得到N-tert-butyl-2-<2(R)-hydroxy-4-phenyl-3(S)-((2(S)-amino-2-3(S)-tetrahydrofuranyl)acetyl)butyl>decahydro-(4aS,8aS)-isoquinoline-3(S)-carboxamide
  参考文献：
  名称：

  Potent HIV protease inhibitors: the development of tetrahydrofuranylglycines as novel P2-ligands and pyrazine amides as P3-ligands

  摘要：

  A series of protease inhibitors bearing constrained unnatural amino acids at the P2-position and novel heterocycles at the P3-position of compound 1 (Ro 31-8959) were synthesized, and their in vitro enzyme inhibitory and antiviral activities were evaluated. Replacement of P2-asparagine of compound 1 with (2S,3'R)-tetrahydrofuranylglycine resulted in improvement in enzyme inhibitory as well as antiviral potencies (compound 23). Interestingly, incorporation of (2S,3'S)-tetrahydrofuranylglycine at the P2-position proved to be less effective. The resulting compound 24 was 100-fold less potent than the 2S,3R-isomer (compound 23). This stereochemical preference indicated a hydrogen-bonding interaction between the tetrahydrofuranyl oxygen and the residues of the S2-region of the enzyme active site. Furthermore, replacement of P3-quinolinoyl ligand of 1 with various novel heterocycles resulted in potent inhibitors of HIV proteases. Of particular interest, compound 2 with (2S,3'R)-tetrahydrofuranylglycine at P2 and pyrazine derivative at P3 is one of the most potent inhibitors of HIV-1 (IC50 value 0.07 nM) and HIV-2 (IC50 value 0.18 nM) proteases. Another important result in this series is the identification of compound 27 in which the P2-P3-amide carbonyl has been removed. The resulting compound 27 has exhibited improvement in antiviral potency while retaining the enzyme inhibitory potency similar to compound 1.

  DOI：

  10.1021/jm00068a006
• 作为产物：
  描述：

  N-tert-butyl-2-<2(R)-hydroxy-4-phenyl-3(S)-azidobutyl>decahydro(4aS,8aS)-isoquinoline-3(S)-carboxamide 在 palladium on activated charcoal N-甲基吗啉 、 氢气 、 1-羟基苯并三唑 、 1-(3-二甲基氨基丙基)-3-乙基碳二亚胺 作用下， 以 四氢呋喃 、 甲醇 、 溶剂黄146 、 N,N-二甲基甲酰胺 为溶剂， 生成 (3S,4aS,8aS)-2-[(2R,3S)-3-((S)-2-Azido-2-(S)-tetrahydro-furan-3-yl-acetylamino)-2-hydroxy-4-phenyl-butyl]-decahydro-isoquinoline-3-carboxylic acid tert-butylamide
  参考文献：
  名称：

  3'-Tetrahydrofuranylglycine as a novel, unnatural amino acid surrogate for asparagine in the design of inhibitors of the HIV protease

  摘要：

  The blockade of the HIV protease has become a major target in the search for an effective therapy for AIDS.1 While many reports of potent HIV-1 inhibitors have appeared recently, the compound Ro 31-8959 remains the least selective for the HIV-1 and HIV-2 proteases.2 This property may result in reduced susceptibility to resistance since these represent the genetically most divergent strains of HIV presently known to exist.

  DOI：

  10.1021/ja00055a069