[1-(4-Aminophenyl)sulfonylpiperidin-2-yl]methanol | 1033132-75-0

• 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: [1-(4-Aminophenyl)sulfonylpiperidin-2-yl]methanol
• CAS: 1033132-75-0
• 化学式: C₁₂H₁₈N₂O₃S
• mdl: MFCD12437920
• 分子量: 270.353
• InChiKey: JTOTXIYQZZVTCD-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.6
• 重原子数：
  18
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  92
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  [1-(4-Aminophenyl)sulfonylpiperidin-2-yl]methanol 、 2-甲基-5三氟甲基-2H-吡唑-3-羧酸 在 吡啶 作用下， 以 二氯甲烷 为溶剂， 以73%的产率得到N-(4-((2-(hydroxymethyl)piperidin-1-yl)sulfonyl)phenyl)-1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide
  参考文献：
  名称：

  Non-nucleoside Inhibitors of the Measles Virus RNA-Dependent RNA Polymerase: Synthesis, Structure–Activity Relationships, and Pharmacokinetics

  摘要：

  The measles virus (MeV), a member of the paramyxovirus family, is an important cause of pediatric morbidity and mortality worldwide. In an effort to provide therapeutic treatments for improved measles management, we previously identified a small, non-nucleoside organic inhibitor of the viral RNA-dependent RNA polymerase by means of high-throughput screening. Subsequent structure-activity relationship (SAR) studies around the corresponding pyrazole carboxamide scaffold led to the discovery of 2 (AS-136a), a first generation lead with low nanomolar potency against life MeV and attractive physical properties suitable for development. However, its poor water solubility and low oral bioavailability (F) in rat suggested that the lead could benefit from further SAR studies to improve the biophysical characteristics of the compound. Optimization of in vitro potency and aqueous solubility led to the discovery of 2o (ERDRP-00519), a potent inhibitor of MeV (EC50 = 60 nM) with an aqueous solubility of approximately 60 mu g/mL. The agent shows a 10-fold exposure (AUC/C-max) increase in the rat model relative to 2, displays near dose proportionality in the range of 10-50 mg/kg and exhibits good oral bioavailability (F = 39%). The significant solubility increase appears linked to the improved oral bioavailability.

  DOI：

  10.1021/jm201699w
• 作为产物：
  描述：

  2-哌啶甲醇 在 palladium on activated charcoal 、 氢气 、 sodium carbonate 作用下， 以 甲醇 、 丙酮 为溶剂， 20.0 ℃ 、344.75 kPa 条件下， 反应 14.0h， 生成 [1-(4-Aminophenyl)sulfonylpiperidin-2-yl]methanol
  参考文献：
  名称：

  Non-nucleoside Inhibitors of the Measles Virus RNA-Dependent RNA Polymerase: Synthesis, Structure–Activity Relationships, and Pharmacokinetics

  摘要：

  The measles virus (MeV), a member of the paramyxovirus family, is an important cause of pediatric morbidity and mortality worldwide. In an effort to provide therapeutic treatments for improved measles management, we previously identified a small, non-nucleoside organic inhibitor of the viral RNA-dependent RNA polymerase by means of high-throughput screening. Subsequent structure-activity relationship (SAR) studies around the corresponding pyrazole carboxamide scaffold led to the discovery of 2 (AS-136a), a first generation lead with low nanomolar potency against life MeV and attractive physical properties suitable for development. However, its poor water solubility and low oral bioavailability (F) in rat suggested that the lead could benefit from further SAR studies to improve the biophysical characteristics of the compound. Optimization of in vitro potency and aqueous solubility led to the discovery of 2o (ERDRP-00519), a potent inhibitor of MeV (EC50 = 60 nM) with an aqueous solubility of approximately 60 mu g/mL. The agent shows a 10-fold exposure (AUC/C-max) increase in the rat model relative to 2, displays near dose proportionality in the range of 10-50 mg/kg and exhibits good oral bioavailability (F = 39%). The significant solubility increase appears linked to the improved oral bioavailability.

  DOI：

  10.1021/jm201699w

文献信息

• Potent Non-Nucleoside Inhibitors of the Measles Virus RNA-Dependent RNA Polymerase Complex
  作者：Aiming Sun、Jeong-Joong Yoon、Yan Yin、Andrew Prussia、Yutao Yang、Jaeki Min、Richard K. Plemper、James P. Snyder

  DOI：10.1021/jm701239a

  日期：2008.7

  Measles virus (MV) is one of the most infectious pathogens known. In spite of the existence of a vaccine, approximately 350000 deaths/year result from MV or associated complications. Antimeasles compounds Could conceivably diminish these statistics and provide a therapy that complements vaccine treatment. We recently described a high-throughput screening hit compound 1 (16677) against MV-infected cells with the capacity to eliminate viral reproduction at 250 nM by inhibiting the action of the virus's RNA-dependent RNA polymerase complex (RdRp). The compound, 1-methyl-3-(trifluoroi-nethyl)-N-[4-sulfonylphenyl]-1H-pyrazole-5-carboxamide, 1 carries a critical CF3 moiety on the 1,2-pyrazole ring. Elaborating on the preliminary structure-activity (SAR) study, the present work presents the synthesis and SAR of a much broader range of low nanomolar nonpeptidic MV inhibitors and speculates on the role of the CF3 functionality.
• Non-nucleoside Inhibitors of the Measles Virus RNA-Dependent RNA Polymerase: Synthesis, Structure–Activity Relationships, and Pharmacokinetics
  作者：J. Maina Ndungu、Stefanie A. Krumm、Dan Yan、Richard F. Arrendale、G. Prabhakar Reddy、Taylor Evers、Randy Howard、Michael G. Natchus、Manohar T. Saindane、Dennis C. Liotta、Richard K. Plemper、James P. Snyder、Aiming Sun

  DOI：10.1021/jm201699w

  日期：2012.5.10

  The measles virus (MeV), a member of the paramyxovirus family, is an important cause of pediatric morbidity and mortality worldwide. In an effort to provide therapeutic treatments for improved measles management, we previously identified a small, non-nucleoside organic inhibitor of the viral RNA-dependent RNA polymerase by means of high-throughput screening. Subsequent structure-activity relationship (SAR) studies around the corresponding pyrazole carboxamide scaffold led to the discovery of 2 (AS-136a), a first generation lead with low nanomolar potency against life MeV and attractive physical properties suitable for development. However, its poor water solubility and low oral bioavailability (F) in rat suggested that the lead could benefit from further SAR studies to improve the biophysical characteristics of the compound. Optimization of in vitro potency and aqueous solubility led to the discovery of 2o (ERDRP-00519), a potent inhibitor of MeV (EC50 = 60 nM) with an aqueous solubility of approximately 60 mu g/mL. The agent shows a 10-fold exposure (AUC/C-max) increase in the rat model relative to 2, displays near dose proportionality in the range of 10-50 mg/kg and exhibits good oral bioavailability (F = 39%). The significant solubility increase appears linked to the improved oral bioavailability.