3-Cyclohexyl-1-dimethylcarbamoylmethyl-2-pyridin-3-yl-1H-indole-6-carboxylic acid | 774214-86-7

• 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-Cyclohexyl-1-dimethylcarbamoylmethyl-2-pyridin-3-yl-1H-indole-6-carboxylic acid
• 英文别名: 3-cyclohexyl-1-[2-(dimethylamino)-2-oxoethyl]-2-pyridin-3-ylindole-6-carboxylic acid
• CAS: 774214-86-7
• 化学式: C₂₄H₂₇N₃O₃
• 分子量: 405.497
• InChiKey: VEBIARNTXNHODZ-UHFFFAOYSA-N

物化性质

• 沸点：
  654.8±55.0 °C(Predicted)
• 密度：
  1.26±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4.3
• 重原子数：
  30
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  75.4
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  3-Cyclohexyl-1-dimethylcarbamoylmethyl-2-pyridin-3-yl-1H-indole-6-carboxylic acid 在 吡啶 、 二碳酸二叔丁酯 、 盐酸羟胺 、 三乙胺 、 N,N-二异丙基乙胺 、 三氟乙酸酐 作用下， 以 甲醇 、 二氯甲烷 、 氯仿 、 N,N-二甲基甲酰胺 为溶剂， 反应 75.0h， 生成
  参考文献：
  名称：

  Development of carboxylic acid replacements in indole-N-acetamide inhibitors of hepatitis C virus NS5B polymerase

  摘要：

  Allosteric inhibition of the hepatitis C virus (HCV) NS5B RNA-dependent RNA polyrnerase enzyme has recently emerged as a viable strategy toward blocking replication of viral RNA in cell-based systems. We report here 2 series of indole-N-acetamides, bearing physicochemically diverse carboxylic acid replacements, which show potent affinity for the NS5B enzyme with reduced potential for formation of glucuronide conjugates. Preliminary optimization of these series furnished compounds that are potent in the blockade of subgenomic HCV RNA replication in HUH-7 cells. (c) 2007 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2007.06.093
• 作为产物：
  描述：

  methyl 2-bromo-3-cyclohexyl-1-[2-(dimethylamino)-2-oxoethyl]-1H-indole-6-carboxylate 在 氢氧化钾 、 四(三苯基膦)钯 、 sodium carbonate 作用下， 以 1,4-二氧六环 、 乙二醇二甲醚 、 乙醇 为溶剂， 反应 30.0h， 生成 3-Cyclohexyl-1-dimethylcarbamoylmethyl-2-pyridin-3-yl-1H-indole-6-carboxylic acid
  参考文献：
  名称：

  Potent Inhibitors of Subgenomic Hepatitis C Virus RNA Replication through Optimization of Indole-N-Acetamide Allosteric Inhibitors of the Viral NS5B Polymerase

  摘要：

  Infections caused by hepatitis C virus (HCV) are a significant world health problem for which novel therapies are in urgent demand. Compounds that block replication of subgenomic HCV RNA in liver cells are of interest because of their demonstrated antiviral effect in the clinic. In followup to our recent report that indole-N-acetamides (e.g., 1) are potent allosteric inhibitors of the HCV NS513 polymerase enzyme, we describe here their optimization as cell-based inhibitors. The crystal structure of 1 bound to NS513 was a guide in the design of a two-dimensional compound array that highlighted that formally zwitterionic inhibitors have strong intracellular potency and that pregnane X receptor (PXR) activation (an undesired off-target activity) is linked to a structural feature of the inhibitor. Optimized analogues devoid of PXR activation (e.g., 55, EC50 = 127 nM) retain strong cell-based efficacy under high serum conditions and show acceptable pharmacokinetics parameters in rat and dog.

  DOI：

  10.1021/jm050056+

文献信息

• Development of carboxylic acid replacements in indole-N-acetamide inhibitors of hepatitis C virus NS5B polymerase
  作者：Ian Stansfield、Marco Pompei、Immacolata Conte、Caterina Ercolani、Giovanni Migliaccio、Mark Jairaj、Claudio Giuliano、Michael Rowley、Frank Narjes

  DOI：10.1016/j.bmcl.2007.06.093

  日期：2007.9

  Allosteric inhibition of the hepatitis C virus (HCV) NS5B RNA-dependent RNA polyrnerase enzyme has recently emerged as a viable strategy toward blocking replication of viral RNA in cell-based systems. We report here 2 series of indole-N-acetamides, bearing physicochemically diverse carboxylic acid replacements, which show potent affinity for the NS5B enzyme with reduced potential for formation of glucuronide conjugates. Preliminary optimization of these series furnished compounds that are potent in the blockade of subgenomic HCV RNA replication in HUH-7 cells. (c) 2007 Elsevier Ltd. All rights reserved.
• Potent Inhibitors of Subgenomic Hepatitis C Virus RNA Replication through Optimization of Indole-<i>N</i>-Acetamide Allosteric Inhibitors of the Viral NS5B Polymerase
  作者：Steven Harper、Salvatore Avolio、Barbara Pacini、Marcello Di Filippo、Sergio Altamura、Licia Tomei、Giacomo Paonessa、Di Marco、Andrea Carfi、Claudio Giuliano、Julio Padron、Fabio Bonelli、Giovanni Migliaccio、Raffaele De Francesco、Ralph Laufer、Michael Rowley、Frank Narjes

  DOI：10.1021/jm050056+

  日期：2005.7.1

  Infections caused by hepatitis C virus (HCV) are a significant world health problem for which novel therapies are in urgent demand. Compounds that block replication of subgenomic HCV RNA in liver cells are of interest because of their demonstrated antiviral effect in the clinic. In followup to our recent report that indole-N-acetamides (e.g., 1) are potent allosteric inhibitors of the HCV NS513 polymerase enzyme, we describe here their optimization as cell-based inhibitors. The crystal structure of 1 bound to NS513 was a guide in the design of a two-dimensional compound array that highlighted that formally zwitterionic inhibitors have strong intracellular potency and that pregnane X receptor (PXR) activation (an undesired off-target activity) is linked to a structural feature of the inhibitor. Optimized analogues devoid of PXR activation (e.g., 55, EC50 = 127 nM) retain strong cell-based efficacy under high serum conditions and show acceptable pharmacokinetics parameters in rat and dog.