4-Acetyl-N-((2R,3S)-3-amino-2-hydroxy-4-phenyl-butyl)-N-isobutyl-benzenesulfonamide | 695815-04-4

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 4-Acetyl-N-((2R,3S)-3-amino-2-hydroxy-4-phenyl-butyl)-N-isobutyl-benzenesulfonamide
• 英文别名: 4-acetyl-N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-N-(2-methylpropyl)benzenesulfonamide
• CAS: 695815-04-4
• 化学式: C₂₂H₃₀N₂O₄S
• 分子量: 418.557
• InChiKey: SKVBUTDDFCIQDT-FCHUYYIVSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.5
• 重原子数：
  29
• 可旋转键数：
  10
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.41
• 拓扑面积：
  109
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  4-Acetyl-N-((2R,3S)-3-amino-2-hydroxy-4-phenyl-butyl)-N-isobutyl-benzenesulfonamide 、 地瑞那韦中间体1 在 三乙胺 作用下， 以 二氯甲烷 为溶剂， 生成 (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl ((2S,3R)-4-((4-acetyl-N-isobutylphenyl)sulfonamido)-3-hydroxy-1-phenylbutan-2-yl)-carbamate
  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
• 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 4-Acetyl-N-((2R,3S)-3-amino-2-hydroxy-4-phenyl-butyl)-N-isobutyl-benzenesulfonamide
  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

• BROADSPECTRUM HETEROCYCLIC SUBSTITUTED PHENYL CONTAINING SULFONAMIDE HIV PROTEASE INHIBITORS
  申请人：Tibotec Pharmaceuticals Ltd.

  公开号：EP1463502A1

  公开（公告）日：2004-10-06
• [EN] BROADSPECTRUM HETEROCYCLIC SUBSTITUTED PHENYL CONTAINING SULFONAMIDE HIV PROTEASE INHIBITORS<br/>[FR] PHENYLE HETEROCYCLIQUE SUBSTITUE A LARGE SPECTRE CONTENANT DES INHIBITEURS DE LA SULFONAMIDE PROTEASE VIH
  申请人：TIBOTEC PHARM LTD

  公开号：WO2003053435A1

  公开（公告）日：2003-07-03

  The present invention concerns the compounds having the formula (I), N-oxides, salts, stereoisomeric forms, racemic mixtures, prodrugs, esters and metabolites thereof, wherein Haryl is an aromatic monocyclic, bicyclic or tricyclic heterocycle having 3 to 14 ring members which contains one or more heteroatom ring members selected from nitrogen, oxygen and sulfur and which may optionally be substituted on (i) one or more carbon atoms by C1-6alkyl, halogen, hydroxy, optionally mono- or disubstituted amino, nitro, cyano, haloC1-6alkyl, carboxyl, C3-7cycloalkyl, optionally mono- or disubstituted aminocarbonyl, methylthio, methylsulfonyl, aryl, -(R7a)n-M-R7b, Het1 and Het2; whereby the optional substituents on any amino function are independently selected from R¿5? and -A-R6; and on (ii) a nitrogen atom if present by hydroxy or -A-R6. It further relates to their use as broadspectrum HIV protease inhibitors, processes for their preparation as well as pharmaceutical compositions and diagnostic kits comprising them. It also concerns combinations thereof with another anti-retroviral agent, and to their use in assays as reference compounds or as reagents.
• 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.