[(1S,2R)-3-(Benzenesulfonyl-isobutyl-amino)-1-benzyl-2-hydroxy-propyl]-carbamic acid tert-butyl ester | 160230-53-5

• 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)-3-(Benzenesulfonyl-isobutyl-amino)-1-benzyl-2-hydroxy-propyl]-carbamic acid tert-butyl ester
• 英文别名: tert-butyl N-[(1S,2R)-3-[benzenesulfonyl(isobutyl)amino]-1-benzyl-2-hydroxy-propyl]carbamate；tert-butyl N-[(2S,3R)-4-[benzenesulfonyl(2-methylpropyl)amino]-3-hydroxy-1-phenylbutan-2-yl]carbamate
• CAS: 160230-53-5
• 化学式: C₂₅H₃₆N₂O₅S
• 分子量: 476.637
• InChiKey: BCMSSYPKHVOCGK-XZOQPEGZSA-N

物化性质

• 密度：
  1.167±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4.5
• 重原子数：
  33
• 可旋转键数：
  12
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.48
• 拓扑面积：
  104
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  [(1S,2R)-3-(Benzenesulfonyl-isobutyl-amino)-1-benzyl-2-hydroxy-propyl]-carbamic acid tert-butyl ester 在 3-dimethoxyphosphoryloxy-1,2,3-benzotriazine-4(3H)-one 、 三乙胺 、 三氟乙酸 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 反应 4.0h， 生成 (S)-N-[(1S,2R)-3-(Benzenesulfonyl-isobutyl-amino)-1-benzyl-2-hydroxy-propyl]-3-methyl-2-(2-oxo-tetrahydro-pyrimidin-1-yl)-butyramide
  参考文献：
  名称：

  Discovery of imidazolidine-2,4-dione-linked HIV protease inhibitors with activity against lopinavir-resistant mutant HIV

  摘要：

  A new series of HIV protease inhibitors has been designed and synthesized based on the combination of the (R)-(hydroxyethylamino)sulfonamide isostere and the cyclic urea component of lopinavir. The series was optimized by replacing the 6-membered cyclic urea linker with an imidazolidine-2,4-dione which readily underwent N-alkylation to incorporate various methylene-linked heterocycle groups that bind favorably in site 3 of HIV protease. Significant improvements compared to lopinavir were seen in cell culture activity versus wild-type virus (pNL4-3) and the lopinavir-resistant mutant virus A17 (generated by in vitro serial passage of HIV-1 (pNL4-3) in NIT-4 cells). Select imidazolidine-2,4-dione containing Pis were also more effective at inhibiting highly resistant patient isolates Pt1 and Pt2 than lopinavir. Pharmacokinetic data collected for compounds in this series varied considerably when coadministered orally in the rat with an equal amount of ritonavir (5 mg/kg each). The AUC values ranged from 0.144 to 12.33 mu g h/mL. (c) 2006 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2006.05.063
• 作为产物：
  描述：

  1-苄基-2,3-环氧正丙基-氨基甲酸叔丁酯 在 三乙胺 作用下， 以 二氯甲烷 为溶剂， 生成 [(1S,2R)-3-(Benzenesulfonyl-isobutyl-amino)-1-benzyl-2-hydroxy-propyl]-carbamic acid tert-butyl 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

• Sulfonamide inhibitors of aspartyl protease
  申请人：Vertex Pharmaceuticals, Incorporated

  公开号：US06372778B1

  公开（公告）日：2002-04-16

  The present invention relates to a novel class of sulfonamides which are aspartyl protease inhibitors. In one embodiment, this invention relates to a novel class of HIV aspartyl protease inhibitors characterized by specific structural and physicochemical features. This invention also relates to pharmaceutical compositions comprising these compounds. The compounds and pharmaceutical compositions of this invention are particularly well suited for inhibiting HIV-1 and HIV-2 protease activity and consequently, may be advantageously used as anti-viral agents against the HIV-1 and HIV-2 viruses. This invention also relates to methods for inhibiting the activity of HIV aspartyl protease using the compounds of this invention and methods for screening compounds for anti-HIV activity.

  本发明涉及一种新型磺胺类化合物，其为天冬氨酸蛋白酶抑制剂。在一个实施例中，本发明涉及一种新型HIV天冬氨酸蛋白酶抑制剂，其具有特定的结构和理化特征。本发明还涉及包含这些化合物的药物组合物。本发明的化合物和药物组合物特别适用于抑制HIV-1和HIV-2蛋白酶活性，因此，可以有利地用作抗HIV-1和HIV-2病毒的抗病毒剂。本发明还涉及使用本发明的化合物抑制HIV天冬氨酸蛋白酶活性的方法，以及筛选具有抗HIV活性的化合物的方法。
• 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.
• Discovery of imidazolidine-2,4-dione-linked HIV protease inhibitors with activity against lopinavir-resistant mutant HIV
  作者：William J. Flosi、David A. DeGoey、David J. Grampovnik、Hui-ju Chen、Larry L. Klein、Tatyana Dekhtyar、Sherie Masse、Kennan C. Marsh、Hong Mei Mo、Dale Kempf

  DOI：10.1016/j.bmc.2006.05.063

  日期：2006.10

  A new series of HIV protease inhibitors has been designed and synthesized based on the combination of the (R)-(hydroxyethylamino)sulfonamide isostere and the cyclic urea component of lopinavir. The series was optimized by replacing the 6-membered cyclic urea linker with an imidazolidine-2,4-dione which readily underwent N-alkylation to incorporate various methylene-linked heterocycle groups that bind favorably in site 3 of HIV protease. Significant improvements compared to lopinavir were seen in cell culture activity versus wild-type virus (pNL4-3) and the lopinavir-resistant mutant virus A17 (generated by in vitro serial passage of HIV-1 (pNL4-3) in NIT-4 cells). Select imidazolidine-2,4-dione containing Pis were also more effective at inhibiting highly resistant patient isolates Pt1 and Pt2 than lopinavir. Pharmacokinetic data collected for compounds in this series varied considerably when coadministered orally in the rat with an equal amount of ritonavir (5 mg/kg each). The AUC values ranged from 0.144 to 12.33 mu g h/mL. (c) 2006 Elsevier Ltd. All rights reserved.