dimethyl (2S,2'S)-1,1'-((2S,3S,5S)-1-(4-(6-cyanopyridin-3-yl)phenyl)-3-hydroxy-6-phenylhexane-2,5-diyl)bis(azanediyl)bis(3,3-dimethyl-1-oxobutane-2,1-diyl)dicarbamate | 1335054-28-8

• 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: dimethyl (2S,2'S)-1,1'-((2S,3S,5S)-1-(4-(6-cyanopyridin-3-yl)phenyl)-3-hydroxy-6-phenylhexane-2,5-diyl)bis(azanediyl)bis(3,3-dimethyl-1-oxobutane-2,1-diyl)dicarbamate
• 英文别名: methyl N-[(1S)-1-[[(1S,3S,4S)-1-benzyl-5-[4-(6-cyano-3-pyridyl)phenyl]-3-hydroxy-4-[[(2S)-2-(methoxycarbonylamino)-3,3-dimethyl-butanoyl]amino]pentyl]carbamoyl]-2,2-dimethyl-propyl]carbamate；methyl N-[(2S)-1-[[(2S,3S,5S)-1-[4-(6-cyanopyridin-3-yl)phenyl]-3-hydroxy-5-[[(2S)-2-(methoxycarbonylamino)-3,3-dimethylbutanoyl]amino]-6-phenylhexan-2-yl]amino]-3,3-dimethyl-1-oxobutan-2-yl]carbamate
• CAS: 1335054-28-8
• 化学式: C₄₀H₅₂N₆O₇
• 分子量: 728.889
• InChiKey: FRUOECDCDJTZCD-KSVMHDQPSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.3
• 重原子数：
  53
• 可旋转键数：
  18
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.45
• 拓扑面积：
  192
• 氢给体数：
  5
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  dimethyl (2S,2'S)-1,1'-((2S,3S,5S)-1-(4-(6-cyanopyridin-3-yl)phenyl)-3-hydroxy-6-phenylhexane-2,5-diyl)bis(azanediyl)bis(3,3-dimethyl-1-oxobutane-2,1-diyl)dicarbamate 在 sodium tetrahydroborate 、 二异丁基氢化铝 作用下， 以 甲醇 、 正己烷 、 二氯甲烷 为溶剂， 反应 3.0h， 生成 dimethyl (2S,2'S)-1,1'-((2S,3S,5S)-3-hydroxy-1-(4-(4-(hydroxymethyl)pyridin-3-yl)phenyl)-6-phenylhexane-2,5-diyl)bis(azanediyl)bis(3,3-dimethyl-1-oxobutane-2,1-diyl)dicarbamate
  参考文献：
  名称：

  P1-Substituted Symmetry-Based Human Immunodeficiency Virus Protease Inhibitors with Potent Antiviral Activity against Drug-Resistant Viruses

  摘要：

  Because there is currently no cure for HIV infection, patients must remain on long-term drug therapy, leading to concerns over potential drug side effects and the emergence of drug resistance. For this reason, new and safe antiretroviral agents with improved potency against drug-resistant strains of HIV are needed. A series of HIV protease inhibitors (PIs) with potent activity against both wild-type (WT) virus and drug-resistant strains of HIV was designed and synthesized. The incorporation of substituents with hydrogen bond donor and acceptor groups at the PI position of our symmetry-based inhibitor series resulted in significant potency improvements against the resistant mutants. By this approach, several compounds, such as 13, 24, and 29, were identified that demonstrated similar or improved potencies compared to 1 against highly mutated strains of HIV derived from patients who previously failed HIV PI therapy. Overall, compound 13 demonstrated the best balance of potency against drug resistant strains of HIV and oral bioavailability in pharmacokinetic studies. X-ray analysis of an HIV PI with an improved resistance profile bound to WT HIV protease is also reported.

  DOI：

  10.1021/jm201109t
• 作为产物：
  描述：

  (4S)-5-[4-(benzyloxy)phenyl]-4-(dibenzylamino)-3-oxopentanenitrile 在 盐酸 、 4-二甲氨基吡啶 、 bis-triphenylphosphine-palladium(II) chloride 、 sodium tetrahydroborate 、 甲烷磺酸 、 palladium 10% on activated carbon 、 甲酸铵 、 sodium carbonate 、 potassium carbonate 、 N,N-二异丙基乙胺 、 3-(二乙氧基邻酰氧基)-1,2,3-苯并三嗪-4-酮 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 乙醚 、 二氯甲烷 、 甲基叔丁基醚 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 81.5h， 生成 dimethyl (2S,2'S)-1,1'-((2S,3S,5S)-1-(4-(6-cyanopyridin-3-yl)phenyl)-3-hydroxy-6-phenylhexane-2,5-diyl)bis(azanediyl)bis(3,3-dimethyl-1-oxobutane-2,1-diyl)dicarbamate
  参考文献：
  名称：

  P1-Substituted Symmetry-Based Human Immunodeficiency Virus Protease Inhibitors with Potent Antiviral Activity against Drug-Resistant Viruses

  摘要：

  Because there is currently no cure for HIV infection, patients must remain on long-term drug therapy, leading to concerns over potential drug side effects and the emergence of drug resistance. For this reason, new and safe antiretroviral agents with improved potency against drug-resistant strains of HIV are needed. A series of HIV protease inhibitors (PIs) with potent activity against both wild-type (WT) virus and drug-resistant strains of HIV was designed and synthesized. The incorporation of substituents with hydrogen bond donor and acceptor groups at the PI position of our symmetry-based inhibitor series resulted in significant potency improvements against the resistant mutants. By this approach, several compounds, such as 13, 24, and 29, were identified that demonstrated similar or improved potencies compared to 1 against highly mutated strains of HIV derived from patients who previously failed HIV PI therapy. Overall, compound 13 demonstrated the best balance of potency against drug resistant strains of HIV and oral bioavailability in pharmacokinetic studies. X-ray analysis of an HIV PI with an improved resistance profile bound to WT HIV protease is also reported.

  DOI：

  10.1021/jm201109t

文献信息

• P1-Substituted Symmetry-Based Human Immunodeficiency Virus Protease Inhibitors with Potent Antiviral Activity against Drug-Resistant Viruses
  作者：David A. DeGoey、David J. Grampovnik、Hui-Ju Chen、William J. Flosi、Larry L. Klein、Tatyana Dekhtyar、Vincent Stoll、Mulugeta Mamo、Akhteruzzaman Molla、Dale J. Kempf

  DOI：10.1021/jm201109t

  日期：2011.10.27

  Because there is currently no cure for HIV infection, patients must remain on long-term drug therapy, leading to concerns over potential drug side effects and the emergence of drug resistance. For this reason, new and safe antiretroviral agents with improved potency against drug-resistant strains of HIV are needed. A series of HIV protease inhibitors (PIs) with potent activity against both wild-type (WT) virus and drug-resistant strains of HIV was designed and synthesized. The incorporation of substituents with hydrogen bond donor and acceptor groups at the PI position of our symmetry-based inhibitor series resulted in significant potency improvements against the resistant mutants. By this approach, several compounds, such as 13, 24, and 29, were identified that demonstrated similar or improved potencies compared to 1 against highly mutated strains of HIV derived from patients who previously failed HIV PI therapy. Overall, compound 13 demonstrated the best balance of potency against drug resistant strains of HIV and oral bioavailability in pharmacokinetic studies. X-ray analysis of an HIV PI with an improved resistance profile bound to WT HIV protease is also reported.