2-(4-Chloro-3-dimethylaminomethyl-phenyl)-3-cyclohexyl-indole-1,6-dicarboxylic acid 1-tert-butyl ester 6-methyl ester | 1027420-98-9

• 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: 2-(4-Chloro-3-dimethylaminomethyl-phenyl)-3-cyclohexyl-indole-1,6-dicarboxylic acid 1-tert-butyl ester 6-methyl ester
• 英文别名: 1-O-tert-butyl 6-O-methyl 2-[4-chloro-3-[(dimethylamino)methyl]phenyl]-3-cyclohexylindole-1,6-dicarboxylate
• CAS: 1027420-98-9
• 化学式: C₃₀H₃₇ClN₂O₄
• 分子量: 525.088
• InChiKey: PVKYLSPYHYHVPD-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  7.8
• 重原子数：
  37
• 可旋转键数：
  8
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.47
• 拓扑面积：
  60.8
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  2-(4-Chloro-3-dimethylaminomethyl-phenyl)-3-cyclohexyl-indole-1,6-dicarboxylic acid 1-tert-butyl ester 6-methyl ester 在 sodium hydride 、 三乙胺 、 三氟乙酸 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 13.67h， 生成 2-(4-Chloro-3-dimethylaminomethyl-phenyl)-3-cyclohexyl-1-dimethylcarbamoylmethyl-1H-indole-6-carboxylic acid methyl ester
  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+
• 作为产物：
  描述：

  2-溴-3-环己基-1H-吲哚-6-羧酸甲酯 在 4-二甲氨基吡啶 、 正丁基锂 作用下， 以 四氢呋喃 、 正己烷 、 二氯甲烷 为溶剂， 反应 13.75h， 生成 2-(4-Chloro-3-dimethylaminomethyl-phenyl)-3-cyclohexyl-indole-1,6-dicarboxylic acid 1-tert-butyl ester 6-methyl ester
  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+