{(1S,2R)-1-Benzyl-2-hydroxy-3-[isobutyl-(toluene-4-sulfonyl)-amino]-propyl}-carbamic acid hexahydro-furo[2,3-b]furan-3-yl ester

• 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: {(1S,2R)-1-Benzyl-2-hydroxy-3-[isobutyl-(toluene-4-sulfonyl)-amino]-propyl}-carbamic acid hexahydro-furo[2,3-b]furan-3-yl ester
• 英文别名: Carbamic acid, [(1S,2R)-2-hydroxy-3-[[(4-methylphenyl)sulfonyl](2-methylpropyl)amino]-1-(phenylmethyl)propyl]-, hexahydrofuro[2,3-b]furan-3-yl ester；2,3,3a,4,5,6a-hexahydrofuro[2,3-b]furan-4-yl N-[(2S,3R)-3-hydroxy-4-[(4-methylphenyl)sulfonyl-(2-methylpropyl)amino]-1-phenylbutan-2-yl]carbamate
• 化学式: C₂₈H₃₈N₂O₇S
• 分子量: 546.685
• InChiKey: SMRBDAAALPUZDJ-OQCZMMSSSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4
• 重原子数：
  38
• 可旋转键数：
  12
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.54
• 拓扑面积：
  123
• 氢给体数：
  2
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  [(1S,2R)-2-羟基-3-[(2-甲基丙基)氨基]-1-(苯基甲基)丙基]-1,1,-二甲基乙酯 在 盐酸 、 三乙胺 作用下， 以 二氯甲烷 、 异丙醇 为溶剂， 生成 {(1S,2R)-1-Benzyl-2-hydroxy-3-[isobutyl-(toluene-4-sulfonyl)-amino]-propyl}-carbamic acid hexahydro-furo[2,3-b]furan-3-yl ester
  参考文献：
  名称：

  Discovery and Selection of TMC114, a Next Generation HIV-1 Protease Inhibitor

  摘要：

  The screening of known HIV-1 protease inhibitors against a panel of multi-drug-resistant viruses revealed the potent activity of TMC126 on drug-resistant mutants. In comparison to amprenavir, the improved affinity of TMC126 is largely the result of one extra hydrogen bond to the backbone of the protein in the P2 pocket. Modification of the substitution pattern on the phenylsulfonamide P2 ' substituent of TMC126 created an interesting SAR, with the close analogue TMC114 being found to have a similar antiviral activity against the mutant and the wild-type viruses. X-ray and thermodynamic studies on both wild-type and mutant enzymes showed an extremely high enthalpy driven affinity of TMC114 for HIV-1 protease. In vitro selection of mutants resistant to TMC 114 starting from wild-type virus proved to be extremely difficult; this was not the case for other close analogues. Therefore, the extra H-bond to the backbone in the P2 pocket cannot be the only explanation for the interesting antiviral profile of TMC114. Absorption studies in animals indicated that TMC114 has pharmacokinetic properties comparable to currently approved HIV-1 protease inhibitors.

  DOI：

  10.1021/jm049560p

文献信息

• Discovery and Selection of TMC114, a Next Generation HIV-1 Protease Inhibitor
  作者：Dominique L. N. G. Surleraux、Abdellah Tahri、Wim G. Verschueren、Geert M. E. Pille、Herman A. de Kock、Tim H. M. Jonckers、Anik Peeters、Sandra De Meyer、Hilde Azijn、Rudi Pauwels、Marie-Pierre de Bethune、Nancy M. King、Moses Prabu-Jeyabalan、Celia A. Schiffer、Piet B. T. P. Wigerinck

  DOI：10.1021/jm049560p

  日期：2005.3.1

  The screening of known HIV-1 protease inhibitors against a panel of multi-drug-resistant viruses revealed the potent activity of TMC126 on drug-resistant mutants. In comparison to amprenavir, the improved affinity of TMC126 is largely the result of one extra hydrogen bond to the backbone of the protein in the P2 pocket. Modification of the substitution pattern on the phenylsulfonamide P2 ' substituent of TMC126 created an interesting SAR, with the close analogue TMC114 being found to have a similar antiviral activity against the mutant and the wild-type viruses. X-ray and thermodynamic studies on both wild-type and mutant enzymes showed an extremely high enthalpy driven affinity of TMC114 for HIV-1 protease. In vitro selection of mutants resistant to TMC 114 starting from wild-type virus proved to be extremely difficult; this was not the case for other close analogues. Therefore, the extra H-bond to the backbone in the P2 pocket cannot be the only explanation for the interesting antiviral profile of TMC114. Absorption studies in animals indicated that TMC114 has pharmacokinetic properties comparable to currently approved HIV-1 protease inhibitors.