t-butyl 2-(4-(trifluoromethyl)phenylsulfonyl-carbamoyl)phenylcarbamate | 1251932-81-6

• 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: t-butyl 2-(4-(trifluoromethyl)phenylsulfonyl-carbamoyl)phenylcarbamate
• CAS: 1251932-81-6
• 化学式: C₁₉H₁₉F₃N₂O₅S
• 分子量: 444.431
• InChiKey: MFIRJIOYOKBJER-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.17
• 重原子数：
  30.0
• 可旋转键数：
  4.0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.26
• 拓扑面积：
  101.57
• 氢给体数：
  2.0
• 氢受体数：
  5.0

反应信息

• 作为反应物：
  描述：

  t-butyl 2-(4-(trifluoromethyl)phenylsulfonyl-carbamoyl)phenylcarbamate 在 吡啶 、 盐酸 、 bis-triphenylphosphine-palladium(II) chloride 、 sodium carbonate 、 三氯氧磷 作用下， 以 1,4-二氧六环 、 乙二醇二甲醚 、 乙醇 、 水 为溶剂， 反应 2.75h， 生成 2-(2-(3-(3-(tert-butyl)ureido)-5-chloro-2-oxo-6-(3-(pyridin-3-yl)benzyl)pyrazin-1(2H)-yl)acetamido)-N-((4-(trifluoromethyl)phenyl)sulfonyl)benzamide
  参考文献：
  名称：

  Achiral Pyrazinone-Based Inhibitors of the Hepatitis C Virus NS3 Protease and Drug-Resistant Variants with Elongated Substituents Directed Toward the S2 Pocket

  摘要：

  Herein we describe the design, synthesis, inhibitory potency, and pharmacokinetic properties of a novel class of achiral peptidomimetic HCV NS3 protease inhibitors. The compounds are based on a dipeptidomimetic pyrazinone glycine P3P2 building block in combination with an aromatic acyl sulfonamide in the P1P1' position. Structure-activity relationship data and molecular modeling support occupancy of the S2 pocket from elongated R-6 substituents on the 2(1H)-pyrazinone core and several inhibitors with improved inhibitory potency down to K-i = 0.11 mu M were identified. A major goal with the design was to produce inhibitors structurally dissimilar to the di- and tripeptide-based HCV protease inhibitors in advanced stages of development for which cross-resistance might be an issue. Therefore, the retained and improved inhibitory potency against the drug-resistant variants A156T, D168V, and R155K further strengthen the potential of this class of inhibitors. A number of the inhibitors were tested in in vitro preclinical profiling assays to evaluate their apparent pharmacokinetic properties. The various R6 substituents were found to have a major influence on solubility, metabolic stability, and cell permeability.

  DOI：

  10.1021/jm301887f
• 作为产物：
  描述：

  4-三氟甲基苯磺酰胺 、 2-(N-叔丁氧羰基氨基)苯甲酸 在 N,N'-羰基二咪唑 、 1,8-二氮杂双环[5.4.0]十一碳-7-烯 作用下， 以 四氢呋喃 为溶剂， 反应 3.0h， 以47%的产率得到t-butyl 2-(4-(trifluoromethyl)phenylsulfonyl-carbamoyl)phenylcarbamate
  参考文献：
  名称：

  Discovery of achiral inhibitors of the hepatitis C virus NS3 protease based on 2(1H)-pyrazinones

  摘要：

  Herein, the design, synthesis and inhibitory potency of a series of novel hepatitis C virus (HCV) NS3 protease inhibitors are presented. These inhibitors are based on a 2(1H)-pyrazinone P3 scaffold in combination with either a P2 phenylglycine or a glycine, and they were evaluated on the wild type as well as on two resistant variants of the enzyme, A156T and D168V. Molecular modelling suggested that the aromatic side-chain of the P2 phenylglycine occupies the same space as the substituent in position 6 on the pyrazinone core. The versatile synthetic route applied for the pyrazinone synthesis made a switch between the two positions easily feasible, resulting in phenyl-or benzyl substituted pyrazinones and leaving glycine as the P2 residue. Of several P1-P1' residues evaluated, an aromatic P1-P1' scaffold was found superior in combination with the new P3-P2 building block. As a result, an entirely new type of achiral and rigidified inhibitors was discovered, with the best of the novel inhibitors having fourfold improved potency compared to the corresponding tripeptide lead. We consider these achiral inhibitors highly suitable as starting points for further optimization. (C) 2010 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2010.06.101

文献信息

• Discovery of pyrazinone based compounds that potently inhibit the drug-resistant enzyme variant R155K of the hepatitis C virus NS3 protease
  作者：Anna Karin Belfrage、Eldar Abdurakhmanov、Eva Åkerblom、Peter Brandt、Anna Oshalim、Johan Gising、Anna Skogh、Johan Neyts、U. Helena Danielson、Anja Sandström

  DOI：10.1016/j.bmc.2016.03.066

  日期：2016.6

  this series showed nanomolar potency against R155K NS3 protease; which generally confer resistance to all HCV NS3 protease inhibitors approved or in clinical trials. These results further strengthen the potential of this novel substance class, being very different to the approved drugs and clinical candidates, in the development of inhibitors less sensitive to drug resistance.

  在本文中，我们介绍了基于2（1H）-吡嗪酮的HCV NS3蛋白酶抑制剂的设计和合成，这些抑制剂在C端具有变化。使用野生型和抗药性酶变体R155K的基因型1a进行生化评估。令人惊讶的是，不含酸性磺酰胺的化合物仍具有良好的抑制作用，从而挑战了我们以前的分子对接模型。此外，该系列中的某些化合物显示出针对R155K 蛋白酶的纳摩尔效价；通常赋予所有已批准或正在临床试验中的HCV 蛋白酶抑制剂抗药性。这些结果进一步增强了这种新物质类别的潜力，这种新物质类别与批准的药物和临床候选药物非常不同，可用于开发对耐药性较不敏感的抑制剂。
• Pan-NS3 protease inhibitors of hepatitis C virus based on an R3-elongated pyrazinone scaffold
  作者：Anna Karin Belfrage、Eldar Abdurakhmanov、Eva Åkerblom、Peter Brandt、Hiba Alogheli、Johan Neyts、U. Helena Danielson、Anja Sandström

  DOI：10.1016/j.ejmech.2018.02.032

  日期：2018.3

  HCV NS3 protease inhibitors and show that elongated R3 urea substituents were associated with increased inhibitory potencies over several NS3 protein variants. The inhibitors are believed to rely on β-sheet mimicking hydrogen bonds which are similar over different genotypes and current drug resistant variants and correspond to the β-sheet interactions of the natural peptide substrate. Inhibitor 36, for

  在本文中，我们介绍了基于2（1 H）-吡嗪酮的HCV NS3蛋白酶抑制剂的设计和合成，并显示了延长的R 3尿素取代基与几种 蛋白变体的抑制能力增强相关。据信抑制剂依赖于模拟氢键的β-折叠，该氢键在不同的基因型和当前的抗药性变体上是相似的，并且对应于天然肽底物的β-折叠相互作用。例如，具有包括环状酰亚胺的尿素取代基的抑制剂36对基因型1a，野生型（K i  = 30 nM）和R155K（K i  = 2 nM）和基因型3a（Ki  = 5 nM）。