3-Cyclopentyl-2-[2-(dimethylamino)-1,3-thiazol-4-yl]-1-methylindole-6-carboxylic acid | 1393928-04-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 英文名称: 3-Cyclopentyl-2-[2-(dimethylamino)-1,3-thiazol-4-yl]-1-methylindole-6-carboxylic acid
• 英文别名: 3-cyclopentyl-2-[2-(dimethylamino)-1,3-thiazol-4-yl]-1-methylindole-6-carboxylic acid
• CAS: 1393928-04-5
• 化学式: C₂₀H₂₃N₃O₂S
• 分子量: 369.488
• InChiKey: ATSASXBCULKXRD-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.7
• 重原子数：
  26
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  86.6
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  Ethyl 3-[4-[(2-amino-2-methylpropanoyl)amino]phenyl]prop-2-enoate 、 3-Cyclopentyl-2-[2-(dimethylamino)-1,3-thiazol-4-yl]-1-methylindole-6-carboxylic acid 在 水 作用下， 以 二甲基亚砜 为溶剂， 生成 3-[4-[[2-[[3-cyclopentyl-2-[2-(dimethylamino)-1,3-thiazol-4-yl]-1-methylindole-6-carbonyl]amino]-2-methylpropanoyl]amino]phenyl]prop-2-enoic acid
  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：

  6-吲哚甲酸 在 bis-triphenylphosphine-palladium(II) chloride 、 N-溴代丁二酰亚胺(NBS) 、 20% Pd(OH)2/C 、 水 、 氢气 、 溴 、 sodium acetate 、 potassium carbonate 、 potassium hydroxide 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 甲醇 、 醋酸异丙酯 、 水 、 N,N-二甲基甲酰胺 为溶剂， 100.0 ℃ 、101.33 kPa 条件下， 反应 65.33h， 生成 3-Cyclopentyl-2-[2-(dimethylamino)-1,3-thiazol-4-yl]-1-methylindole-6-carboxylic acid
  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.