1h-Indole-6-carboxylic acid,2-(6-amino-2-pyridinyl)-3-cyclopentyl-1-methyl- | 494799-83-6

• 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: 1h-Indole-6-carboxylic acid,2-(6-amino-2-pyridinyl)-3-cyclopentyl-1-methyl-
• 英文别名: 2-(6-aminopyridin-2-yl)-3-cyclopentyl-1-methylindole-6-carboxylic acid
• CAS: 494799-83-6
• 化学式: C₂₀H₂₁N₃O₂
• 分子量: 335.406
• InChiKey: LSEUHWVGRQAOFS-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.8
• 重原子数：
  25
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.3
• 拓扑面积：
  81.1
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  1h-Indole-6-carboxylic acid,2-(6-amino-2-pyridinyl)-3-cyclopentyl-1-methyl- 在 乙酸酐 、 O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate 、 溶剂黄146 、 三乙胺 作用下， 以 二甲基亚砜 、 甲苯 为溶剂， 反应 1.05h， 生成
  参考文献：
  名称：

  Discovery of BI 207524, an Indole Diamide NS5B Thumb Pocket 1 Inhibitor with Improved Potency for the Potential Treatment of Chronic Hepatitis C Virus Infection

  摘要：

  The development of interferon-free regimens for the treatment of chronic HCV infection constitutes a preferred option that is expected in the future to provide patients with improved efficacy, better tolerability, and reduced risk for emergence of drug-resistant virus. We have pursued non-nucleoside NS5B polymerase allosteric inhibitors as combination partners with other direct acting antivirals (DAAs) having a complementary mechanism of action. Herein, we describe the discovery of a potent follow-up compound (BI 207524, 27) to the first thumb pocket 1 NS5B inhibitor to demonstrate antiviral activity in genotype 1 HCV infected patients, BILB 1941 (1). Cell-based replicon potency was significantly improved through electronic modulation of the pKa of the carboxylic acid function of the lead molecule. Subsequent ADME-PK optimization lead to 27, a predicted low clearance compound in man. The preclinical profile of inhibitor 27 is discussed, as well as the identification of a genotoxic metabolite that led to the discontinuation of the development of this compound.

  DOI：

  10.1021/jm501532z
• 作为产物：
  描述：

  6-吲哚甲酸 在 正丁基锂 、 20% Pd(OH)2/C 、 水 、 氢气 、 溴 、 sodium acetate 、 palladium diacetate 、 potassium carbonate 、 三对苯甲基膦 、 potassium hydroxide 、 sodium hydroxide 作用下， 以 四氢呋喃 、 甲醇 、 正己烷 、 醋酸异丙酯 、 水 、 N,N-二甲基甲酰胺 为溶剂， -71.0~75.0 ℃ 、101.33 kPa 条件下， 反应 48.67h， 生成 1h-Indole-6-carboxylic acid,2-(6-amino-2-pyridinyl)-3-cyclopentyl-1-methyl-
  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 BI 207524, an Indole Diamide NS5B Thumb Pocket 1 Inhibitor with Improved Potency for the Potential Treatment of Chronic Hepatitis C Virus Infection
  作者：Pierre L. Beaulieu、Paul C. Anderson、Richard Bethell、Michael Bös、Yves Bousquet、Christian Brochu、Michael G. Cordingley、Gulrez Fazal、Michel Garneau、James R. Gillard、Stephen Kawai、Martin Marquis、Ginette McKercher、Marc-André Poupart、Timothy Stammers、Bounkham Thavonekham、Dominik Wernic、Jianmin Duan、George Kukolj

  DOI：10.1021/jm501532z

  日期：2014.12.11

  The development of interferon-free regimens for the treatment of chronic HCV infection constitutes a preferred option that is expected in the future to provide patients with improved efficacy, better tolerability, and reduced risk for emergence of drug-resistant virus. We have pursued non-nucleoside NS5B polymerase allosteric inhibitors as combination partners with other direct acting antivirals (DAAs) having a complementary mechanism of action. Herein, we describe the discovery of a potent follow-up compound (BI 207524, 27) to the first thumb pocket 1 NS5B inhibitor to demonstrate antiviral activity in genotype 1 HCV infected patients, BILB 1941 (1). Cell-based replicon potency was significantly improved through electronic modulation of the pKa of the carboxylic acid function of the lead molecule. Subsequent ADME-PK optimization lead to 27, a predicted low clearance compound in man. The preclinical profile of inhibitor 27 is discussed, as well as the identification of a genotoxic metabolite that led to the discontinuation of the development of this compound.
• 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.