((2S,3R)-3-hydroxy-4-(4-hydroxy-N-isobutylphenylsulfonamido)-1-phenylbutan-2-yl)carbamic acid tert-butyl ester | 622865-58-1

• 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: ((2S,3R)-3-hydroxy-4-(4-hydroxy-N-isobutylphenylsulfonamido)-1-phenylbutan-2-yl)carbamic acid tert-butyl ester
• 英文别名: {(1S,2R)-1-Benzyl-2-hydroxy-3-[(4-hydroxy-benzenesulfonyl)-isobutyl-amino]-propyl}-carbamic acid tert-butyl ester；tert-butyl N-[(2S,3R)-3-hydroxy-4-[(4-hydroxyphenyl)sulfonyl-(2-methylpropyl)amino]-1-phenylbutan-2-yl]carbamate
• CAS: 622865-58-1
• 化学式: C₂₅H₃₆N₂O₆S
• 分子量: 492.637
• InChiKey: GJVBJIYLPSPHPV-XZOQPEGZSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.2
• 重原子数：
  34
• 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：
  125
• 氢给体数：
  3
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  ((2S,3R)-3-hydroxy-4-(4-hydroxy-N-isobutylphenylsulfonamido)-1-phenylbutan-2-yl)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)-1-Benzyl-2-hydroxy-3-[(4-hydroxy-benzenesulfonyl)-isobutyl-amino]-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：

  [(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 4-二甲氨基吡啶 、 氢气 、 palladium diacetate 、 N,N-二异丙基乙胺 作用下， 以 四氢呋喃 、 乙醇 、 乙酸乙酯 为溶剂， 25.0 ℃ 、3.0 MPa 条件下， 反应 18.0h， 生成 ((2S,3R)-3-hydroxy-4-(4-hydroxy-N-isobutylphenylsulfonamido)-1-phenylbutan-2-yl)carbamic acid tert-butyl ester
  参考文献：
  名称：

  含有吡咯烷衍生 P2 配体的新型 HIV-1 蛋白酶抑制剂的设计、合成和生物学评价，以对抗耐药变体

  摘要：

  描述了一系列新型 HIV-1 蛋白酶抑制剂的设计、合成和生物学评价，这些抑制剂含有吡咯烷，具有不同的接头作为 P2 配体和各种芳香族衍生物作为 P2' 配体。许多抑制剂在酶和细胞测定中都表现出强大的功效，以及相对较低的细胞毒性。特别是，具有 ( R )-吡咯烷-3-甲酰胺 P2 配体和 4-羟基苯基 P2' 配体的抑制剂34b显示出异常的酶抑制活性，IC 50值为 0.32 nM。此外， 34b还对野生型 HIV-1 和具有低微摩尔 EC 50的耐药变体表现出强大的抗病毒活性值。此外，分子模型研究揭示了抑制剂34b与野生型和耐药 HIV-1 蛋白酶的骨架残基之间的广泛相互作用。这些结果表明利用吡咯烷衍生物作为P2配体的可行性，为进一步设计和优化高效HIV-1蛋白酶抑制剂提供了有价值的信息。

  DOI：

  10.1016/j.ejmech.2023.115389

文献信息

• Design, synthesis and biological evaluation of protease inhibitors containing morpholine cores with remarkable potency against both HIV-1 subtypes B and C
  作者：Mei Zhu、Huiyu Zhou、Ling Ma、Biao Dong、Jiwei Ding、Jinming Zhou、Juxian Wang、Guoning Zhang、Minghua Wang、Qi Shan、Shan Cen、Yucheng Wang

  DOI：10.1016/j.ejmech.2022.114251

  日期：2022.4

  impressive in vivo antiviral activity with EC50 value of 89 nM and a degree of inhibitory potency against the DRV-resistant variant. More importantly, 1e exhibits remarkable activity with EC50 values of 13.59 nM and 8.23 nM against subtype C HIV-1 strains ZM246 and Indie, respectively. Furthermore, the in silico studies provide molecular insights into binding features of inhibitors with HIV-1 protease, and

  通过跟进优化胺基HIV-1蛋白酶抑制剂的设计载体，我们设计并生物学评估了一类新型抑制剂，其中吗啉核心中的游离氮或砜作为P2配体与多种取代的苯磺酰胺P2'配体组合. 事实证明，这些抑制剂中的大多数在低纳摩尔范围内表现出显着的酶抑制活性，具有相对较低的细胞毒性。特别是，含有吗啉甲酰胺 P2 配体和 4-羟基苯磺酰胺 P2' 配体的抑制剂1e显示了 90 pM 的稳健酶抑制 IC 50值。此外，1e与 EC 50表现出令人印象深刻的体内抗病毒活性89 nM 的值和对 DRV 抗性变体的一定程度的抑制效力。更重要的是，1e对 C 亚型 HIV-1 毒株 ZM246 和 Indie表现出显着的活性，EC 50值分别为 13.59 nM 和 8.23 nM。此外，计算机研究提供了有关抑制剂与 HIV-1 蛋白酶结合特征的分子见解，并为进一步的过程提供了有价值的预测。
• Cellular accumulation of phosphonate analogs of hiv protease inhibitor compounds
  申请人：Arimilli N. Murty

  公开号：US20070010489A1

  公开（公告）日：2007-01-11

  Phosphonate substituted compounds with HIV protease inhibitory properties having use as therapeutics and for other industrial purposes are disclosed. The compositions inhibit 5 HIV protease activity and/or are useful therapeutically for the treatment of AIDS and other antiviral infections, as well as in assays for the detection of HIV protease.

  本发明揭示了具有HIV蛋白酶抑制剂性质的膦酸酯取代化合物，其具有作为治疗剂和其他工业用途的用途。该组合物抑制5型HIV蛋白酶活性和/或在治疗艾滋病和其他抗病毒感染方面具有治疗作用，以及在检测HIV蛋白酶方面的检测中有用。
• Method and compositions for identifying anti-hiv therapeutic compounds
  申请人：Birkus Gabriel

  公开号：US20070190523A1

  公开（公告）日：2007-08-16

  The invention relates to methods and compositions for identifying compounds having therapeutic activity against human immunodeficiency virus (HIV).

  本发明涉及用于鉴定具有治疗人类免疫缺陷病毒（HIV）活性的化合物的方法和组合物。
• US7649015B2
  申请人：——

  公开号：US7649015B2

  公开（公告）日：2010-01-19
• 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.