3-cyclohexyl-1-[2-(dimethylamino)-2-oxoethyl]-2-(3-furyl)-1H-indole-6-carboxylic acid | 735283-86-0

• 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-[2-(dimethylamino)-2-oxoethyl]-2-(3-furyl)-1H-indole-6-carboxylic acid
• 英文别名: 3-Cyclohexyl-1-dimethylcarbamoylmethyl-2-furan-3-yl-1H-indole-6-carboxylic acid；3-cyclohexyl-1-[2-(dimethylamino)-2-oxoethyl]-2-(furan-3-yl)indole-6-carboxylic acid
• CAS: 735283-86-0
• 化学式: C₂₃H₂₆N₂O₄
• 分子量: 394.47
• InChiKey: WMWCGYUJKNEVBP-UHFFFAOYSA-N

物化性质

• 沸点：
  625.3±55.0 °C(Predicted)
• 密度：
  1.28±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4.4
• 重原子数：
  29
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.39
• 拓扑面积：
  75.7
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  3-cyclohexyl-1-[2-(dimethylamino)-2-oxoethyl]-2-(3-furyl)-1H-indole-6-carboxylic acid 、 N,N-二甲基磺酰胺 在 4-二甲氨基吡啶 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 生成 3-cyclohexyl-1-[2-(dimethylamino)-2-oxoethyl]-N-(dimethylsulfamoyl)-2-(furan-3-yl)indole-6-carboxamide
  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-[2-(dimethylamino)-2-oxoethyl]-2-(3-furyl)-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

• N-Acetamideindolecarboxylic acid allosteric ‘finger-loop’ inhibitors of the hepatitis C virus NS5B polymerase: discovery and initial optimization studies
  作者：Pierre L. Beaulieu、Eric Jolicoeur、James Gillard、Christian Brochu、René Coulombe、Nathalie Dansereau、Jianmin Duan、Michel Garneau、Araz Jakalian、Peter Kühn、Lisette Lagacé、Steven LaPlante、Ginette McKercher、Stéphane Perrault、Martin Poirier、Marc-André Poupart、Timothy Stammers、Louise Thauvette、Bounkham Thavonekham、George Kukolj

  DOI：10.1016/j.bmcl.2009.12.101

  日期：2010.2

  SAR studies at the N1-position of allosteric indole-based HCV NS5B inhibitors has led to the discovery of acetamide derivatives with good cellular potency in subgenomic replicons (EC50 <200 nM). This class of inhibitors displayed improved physicochemical properties and favorable ADME-PK profiles over previously described analogs in this class.

  对基于别构吲哚的 HCV NS5B 抑制剂的 N 1位进行的SAR 研究导致发现在亚基因组复制子中具有良好细胞效力的乙酰胺衍生物 (EC 50 <200 nM)。与先前描述的此类类似物相比，此类抑制剂显示出改善的物理化学性质和有利的 ADME-PK 谱。
• [EN] INDOLE ACETAMIDES AS INHIBITORS OF THE HEPATITIS C VIRUS NS5B POLYMERASE<br/>[FR] ACETAMIDES D'INDOLE COMME INHIBITEURS DE LA POLYMERASE NS5B DU VIRUS DE L'HEPATITE C
  申请人：ANGELETTI P IST RICHERCHE BIO

  公开号：WO2004087714A1

  公开（公告）日：2004-10-14

  The present invention relates to indole and azaindole compounds of formula (I): wherein X1, X2, X3, X4, A1, Ar1, R1, R2 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的定义如本文所述，以及其药用盐，用于预防和治疗丙型肝炎感染。
• 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。
• Ｃ型肝炎ウイルスＮＳ５Ｂポリメラーゼの阻害剤としてのインドールアセトアミド
  申请人：イステイチユート・デイ・リチエルケ・デイ・ビオロジア・モレコラーレ・ピ・アンジエレツテイ・エツセ・ピー・アー

  公开号：JP2007516158A

  公开（公告）日：2007-06-21

  本発明は、Ｃ型肝炎感染の予防および治療において有用な、式（Ｉ）のインドールおよびアザインドール化合物（式中、Ｘ１、Ｘ２、Ｘ３、Ｘ４、Ａ１、Ａｒ１、Ｒ１、Ｒ２およびｎはここで定義された通りである）およびこれらの医薬適合性の塩に関する。

  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）及其药用盐，可用于预防和治疗丙型肝炎感染。
• EP1613634A1
  申请人：——

  公开号：EP1613634A1

  公开（公告）日：2006-01-11