tert-butyl ((2S,3R)-4-((4-acetyl-N-isobutylphenyl)sulfonamido)-3-hydroxy-1-phenylbutan-2-yl)carbamate | 553644-88-5

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: tert-butyl ((2S,3R)-4-((4-acetyl-N-isobutylphenyl)sulfonamido)-3-hydroxy-1-phenylbutan-2-yl)carbamate
• 英文别名: tert-butyl N-[(2S,3R)-4-[(4-acetylphenyl)sulfonyl-(2-methylpropyl)amino]-3-hydroxy-1-phenylbutan-2-yl]carbamate
• CAS: 553644-88-5
• 化学式: C₂₇H₃₈N₂O₆S
• 分子量: 518.675
• InChiKey: KQDOAMFWCZJXNW-LOSJGSFVSA-N

物化性质

• 密度：
  1.179±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4.2
• 重原子数：
  36
• 可旋转键数：
  13
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.48
• 拓扑面积：
  121
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  tert-butyl ((2S,3R)-4-((4-acetyl-N-isobutylphenyl)sulfonamido)-3-hydroxy-1-phenylbutan-2-yl)carbamate 在 盐酸 作用下， 以 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
• 作为产物：
  描述：

  1-苄基-2,3-环氧正丙基-氨基甲酸叔丁酯 在 sodium carbonate 作用下， 以 乙醇 、 水 、 乙酸乙酯 为溶剂， 反应 21.0h， 生成 tert-butyl ((2S,3R)-4-((4-acetyl-N-isobutylphenyl)sulfonamido)-3-hydroxy-1-phenylbutan-2-yl)carbamate
  参考文献：
  名称：

  整合了立体化学定义的P2'配体的HIV-1蛋白酶抑制剂可优化底物信封中的氢键。

  摘要：

  结构导向的设计策略用于通过优化氢键和范德华与蛋白酶的相互作用，同时保留在底物包膜内来改善HIV-1蛋白酶抑制剂的抗药性。探索了4-（1-羟乙基）苯和4-（1,2-二羟乙基）苯部分的立体异构体，作为P2'配体，在P2'提供了一对非对映异构体差向异构体，这些异构体根据羟基的构型表现出不同的效能曲线和P1'组的大小。尽管具有4-（1-羟乙基）苯P2'部分的化合物对一组具有多重耐药性的HIV-1菌株保持了出色的抗病毒效力，但具有极性4-（1,2-二羟乙基）苯部分的类似物的效力较弱，并且只有（R）-受体具有更大的2-乙基丁基P1' 组显示出增强的效力。蛋白酶抑制剂复合物的晶体结构显示羟乙基的（R）-和（S）-立体异构体与Asp30'的强氢键相互作用。值得注意的是，（R）-二羟乙基参与与Asp29′和Asp30′的主链酰胺直接氢键相互作用的独特模式。SAR数据和晶体结构分析为优化这些有前途的HIV-1蛋白酶抑制剂提供了见识。

  DOI：

  10.1021/acs.jmedchem.9b00838

文献信息

• Design, Synthesis, Biological Evaluation, and X-ray Studies of HIV-1 Protease Inhibitors with Modified P2′ Ligands of Darunavir
  作者：Arun K. Ghosh、W. Sean Fyvie、Margherita Brindisi、Melinda Steffey、Johnson Agniswamy、Yuan-Fang Wang、Manabu Aoki、Masayuki Amano、Irene T. Weber、Hiroaki Mitsuya

  DOI：10.1002/cmdc.201700614

  日期：2017.12.7

  antivirals: We report the structure-based design, synthesis, biological evaluation, and X-ray structural studies of a series of highly potent HIV-1 protease inhibitors containing novel P2′ ligands to interact with protease active site residues. The inhibitors were designed to enhance backbone binding interactions, particularly at the S2′ subsite. A number of inhibitors displayed very potent enzyme inhibitory

  结构化抗病毒剂：我们报道了一系列高效的HIV-1蛋白酶抑制剂的结构化设计，合成，生物学评估和X射线结构研究，这些抑制剂含有新型P2'配体以与蛋白酶活性位点残基相互作用。设计抑制剂以增强主链结合相互作用，特别是在S2'亚位点。许多抑制剂表现出非常强的酶抑制和抗病毒活性，并且对达那韦抗性HIV-1变体仍然非常有效。X射线晶体学研究揭示了S2'子位点的关键相互作用。
• HIV-1 Protease Inhibitors Incorporating Stereochemically Defined P2′ Ligands To Optimize Hydrogen Bonding in the Substrate Envelope
  作者：Linah N. Rusere、Gordon J. Lockbaum、Sook-Kyung Lee、Mina Henes、Klajdi Kosovrasti、Ean Spielvogel、Ellen A. Nalivaika、Ronald Swanstrom、Nese Kurt Yilmaz、Celia A. Schiffer、Akbar Ali

  DOI：10.1021/acs.jmedchem.9b00838

  日期：2019.9.12

  analogues with the polar 4-(1,2-dihydroxyethyl)benzene moiety were less potent, and only the (R)-epimer incorporating a larger 2-ethylbutyl P1' group showed improved potency. Crystal structures of protease-inhibitor complexes revealed strong hydrogen bonding interactions of both (R)- and (S)-stereoisomers of the hydroxyethyl group with Asp30'. Notably, the (R)-dihydroxyethyl group was involved in a unique

  结构导向的设计策略用于通过优化氢键和范德华与蛋白酶的相互作用，同时保留在底物包膜内来改善HIV-1蛋白酶抑制剂的抗药性。探索了4-（1-羟乙基）苯和4-（1,2-二羟乙基）苯部分的立体异构体，作为P2'配体，在P2'提供了一对非对映异构体差向异构体，这些异构体根据羟基的构型表现出不同的效能曲线和P1'组的大小。尽管具有4-（1-羟乙基）苯P2'部分的化合物对一组具有多重耐药性的HIV-1菌株保持了出色的抗病毒效力，但具有极性4-（1,2-二羟乙基）苯部分的类似物的效力较弱，并且只有（R）-受体具有更大的2-乙基丁基P1' 组显示出增强的效力。蛋白酶抑制剂复合物的晶体结构显示羟乙基的（R）-和（S）-立体异构体与Asp30'的强氢键相互作用。值得注意的是，（R）-二羟乙基参与与Asp29′和Asp30′的主链酰胺直接氢键相互作用的独特模式。SAR数据和晶体结构分析为优化这些有前途的HIV-1蛋白酶抑制剂提供了见识。
• 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.