3-Cyclohexyl-2-(3-dimethylaminomethyl-phenyl)-1-dimethylcarbamoylmethyl-1H-indole-6-carboxylic acid

• 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-2-(3-dimethylaminomethyl-phenyl)-1-dimethylcarbamoylmethyl-1H-indole-6-carboxylic acid
• 英文别名: 3-cyclohexyl-2-[3-[(dimethylamino)methyl]phenyl]-1-[2-(dimethylamino)-2-oxoethyl]indole-6-carboxylic acid
• 化学式: C₂₈H₃₅N₃O₃
• 分子量: 461.604
• InChiKey: BNGVYMYRSHIVNQ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.9
• 重原子数：
  34
• 可旋转键数：
  7
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.43
• 拓扑面积：
  65.8
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  methyl 2-bromo-3-cyclohexyl-1-[2-(dimethylamino)-2-oxoethyl]-1H-indole-6-carboxylate 在 四(三苯基膦)钯 、 三溴化硼 、 三乙酰氧基硼氢化钠 、 sodium carbonate 、 三乙胺 作用下， 以 乙二醇二甲醚 、 乙醇 、 二氯甲烷 、 1,2-二氯乙烷 为溶剂， 反应 14.0h， 生成 3-Cyclohexyl-2-(3-dimethylaminomethyl-phenyl)-1-dimethylcarbamoylmethyl-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

• Indole acetamides as inhibitors of the hepatitis c virus ns5b polymerase
  申请人：Avolio Salvatore

  公开号：US20070167447A1

  公开（公告）日：2007-07-19

  The present invention relates to indole and azaindole compounds of formula (I): wherein X 1 , X 2 , X 3 , X 4 , A 1 , Ar 1 , R 1 , R 2 and n are as defined herein, and pharmaceutically acceptable salts thereof, useful in the prevention and treatment of hepatitis C infections.

  本发明涉及式(I)的吲哚和氮杂吲哚化合物：其中X1，X2，X3，X4，A1，Ar1，R1，R2和n如本文所定义，并且其药学上可接受的盐，在预防和治疗丙型肝炎感染方面有用。
• 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.