(E)-3-{4-[((S)-3-amino-1-methylpyrrolidine-3-carbonyl)-amino]phenyl}acrylic acid ethyl ester | 1393928-29-4

• 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: (E)-3-{4-[((S)-3-amino-1-methylpyrrolidine-3-carbonyl)-amino]phenyl}acrylic acid ethyl ester
• 英文别名: ethyl (E)-3-[4-[[(3S)-3-amino-1-methylpyrrolidine-3-carbonyl]amino]phenyl]prop-2-enoate
• CAS: 1393928-29-4
• 化学式: C₁₇H₂₃N₃O₃
• 分子量: 317.388
• InChiKey: KZLNIRYOQKFNMN-NADMHLTPSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.9
• 重原子数：
  23
• 可旋转键数：
  6
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.41
• 拓扑面积：
  84.7
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  3-cyclopentyl-1-methyl-2-pyridin-2-yl-1H-indole-6-carboxylic acid 、 (E)-3-{4-[((S)-3-amino-1-methylpyrrolidine-3-carbonyl)-amino]phenyl}acrylic acid ethyl ester 以 二甲基亚砜 为溶剂， 生成
  参考文献：
  名称：

  Discovery of the First Thumb Pocket 1 NS5B Polymerase Inhibitor (BILB 1941) with Demonstrated Antiviral Activity in Patients Chronically Infected with Genotype 1 Hepatitis C Virus (HCV)

  摘要：

  Combinations of direct acting antivirals (DAAs) that have the potential to suppress emergence of resistant virus and that can be used in interferon-sparing regimens represent a preferred option for the treatment of chronic HCV infection. We have discovered allosteric (thumb pocket 1) non-nucleoside inhibitors of HCV NS5B polymerase that inhibit replication in replicon systems. Herein, we report the late-stage optimization of indole-based inhibitors, which began with the identification of a metabolic liability common to many previously reported inhibitors in this series. By use of parallel synthesis techniques, a sparse matrix of inhibitors was generated that provided a collection of inhibitors satisfying potency criteria and displaying improved in vitro ADME profiles. "Cassette" screening for oral absorption in rat provided a short list of potential development candidates. Further evaluation led to the discovery of the first thumb pocket 1 NS5B inhibitor (BILB 1941) that demonstrated antiviral activity in patients chronically infected with genotype 1 HCV.

  DOI：

  10.1021/jm3006788
• 作为产物：
  描述：

  在 2,4,6-三甲基吡啶 、 N-羟基-7-氮杂苯并三氮唑 、 sodium cyanoborohydride 、 1,8-二氮杂双环[5.4.0]十一碳-7-烯 、 Methanaminium,N-[(dimethylamino)(3H-1,2,3-triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methyl-, hexafluorophosphate(1-) 作用下， 以 四氢呋喃 、 乙醇 、 水 、 溶剂黄146 、 N,N-二甲基甲酰胺 为溶剂， 反应 1.0h， 生成 (E)-3-{4-[((S)-3-amino-1-methylpyrrolidine-3-carbonyl)-amino]phenyl}acrylic acid ethyl ester
  参考文献：
  名称：

  Discovery of the First Thumb Pocket 1 NS5B Polymerase Inhibitor (BILB 1941) with Demonstrated Antiviral Activity in Patients Chronically Infected with Genotype 1 Hepatitis C Virus (HCV)

  摘要：

  Combinations of direct acting antivirals (DAAs) that have the potential to suppress emergence of resistant virus and that can be used in interferon-sparing regimens represent a preferred option for the treatment of chronic HCV infection. We have discovered allosteric (thumb pocket 1) non-nucleoside inhibitors of HCV NS5B polymerase that inhibit replication in replicon systems. Herein, we report the late-stage optimization of indole-based inhibitors, which began with the identification of a metabolic liability common to many previously reported inhibitors in this series. By use of parallel synthesis techniques, a sparse matrix of inhibitors was generated that provided a collection of inhibitors satisfying potency criteria and displaying improved in vitro ADME profiles. "Cassette" screening for oral absorption in rat provided a short list of potential development candidates. Further evaluation led to the discovery of the first thumb pocket 1 NS5B inhibitor (BILB 1941) that demonstrated antiviral activity in patients chronically infected with genotype 1 HCV.

  DOI：

  10.1021/jm3006788

文献信息

• Discovery of the First Thumb Pocket 1 NS5B Polymerase Inhibitor (BILB 1941) with Demonstrated Antiviral Activity in Patients Chronically Infected with Genotype 1 Hepatitis C Virus (HCV)
  作者：Pierre L. Beaulieu、Michael Bös、Michael G. Cordingley、Catherine Chabot、Gulrez Fazal、Michel Garneau、James R. Gillard、Eric Jolicoeur、Steven LaPlante、Ginette McKercher、Martin Poirier、Marc-André Poupart、Youla S. Tsantrizos、Jianmin Duan、George Kukolj

  DOI：10.1021/jm3006788

  日期：2012.9.13

  Combinations of direct acting antivirals (DAAs) that have the potential to suppress emergence of resistant virus and that can be used in interferon-sparing regimens represent a preferred option for the treatment of chronic HCV infection. We have discovered allosteric (thumb pocket 1) non-nucleoside inhibitors of HCV NS5B polymerase that inhibit replication in replicon systems. Herein, we report the late-stage optimization of indole-based inhibitors, which began with the identification of a metabolic liability common to many previously reported inhibitors in this series. By use of parallel synthesis techniques, a sparse matrix of inhibitors was generated that provided a collection of inhibitors satisfying potency criteria and displaying improved in vitro ADME profiles. "Cassette" screening for oral absorption in rat provided a short list of potential development candidates. Further evaluation led to the discovery of the first thumb pocket 1 NS5B inhibitor (BILB 1941) that demonstrated antiviral activity in patients chronically infected with genotype 1 HCV.