14-cyclohexyl-7-{[2-(dimethylamino)ethyl](ethyl)amino}-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-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: 14-cyclohexyl-7-{[2-(dimethylamino)ethyl](ethyl)amino}-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylic acid
• 英文别名: 19-cyclohexyl-10-[2-(dimethylamino)ethyl-ethylamino]-8-oxa-12-azatetracyclo[10.7.0.02,7.013,18]nonadeca-1(19),2,4,6,13(18),14,16-heptaene-15-carboxylic acid
• 化学式: C₃₀H₃₉N₃O₃
• 分子量: 489.658
• InChiKey: AOEOKUMYSFDNNQ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.6
• 重原子数：
  36
• 可旋转键数：
  7
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  57.9
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  methyl 14-cyclohexyl-7-oxo-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate 在 水 、 三乙酰氧基硼氢化钠 、 sodium cyanoborohydride 、 溶剂黄146 、 potassium hydroxide 作用下， 以 1,4-二氧六环 、 甲醇 、 二氯甲烷 、 水 、 1,2-二氯乙烷 为溶剂， 反应 10.0h， 生成 14-cyclohexyl-7-{[2-(dimethylamino)ethyl](ethyl)amino}-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylic acid
  参考文献：
  名称：

  Discovery of (7R)-14-Cyclohexyl-7-{[2-(dimethylamino)ethyl](methyl) amino}-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylic Acid (MK-3281), a Potent and Orally Bioavailable Finger-Loop Inhibitor of the Hepatitis C Virus 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. The polymerase of HCV is responsible for the replication of viral genome and has been a prime target for drug discovery efforts. Here, we report on the further development of tetracyclic indole inhibitors, binding to an allosteric site on the thumb domain. Structure-activity relationship (SAR) studies around an indolo-benzoxazocine scaffold led to the identification of compound 33 (MK-3281), an inhibitor with good potency in the HCV subgenomic replication assay and attractive molecular properties suitable for a clinical candidate. The compound caused a consistent decrease in viremia in vivo using the chimeric mouse model of HCV infection.

  DOI：

  10.1021/jm1013105

文献信息

• US7795247B2
  申请人：——

  公开号：US7795247B2

  公开（公告）日：2010-09-14
• Discovery of (7<i>R</i>)-14-Cyclohexyl-7-{[2-(dimethylamino)ethyl](methyl) amino}-7,8-dihydro-6<i>H</i>-indolo[1,2-<i>e</i>][1,5]benzoxazocine-11-carboxylic Acid (MK-3281), a Potent and Orally Bioavailable Finger-Loop Inhibitor of the Hepatitis C Virus NS5B Polymerase
  作者：Frank Narjes、Benedetta Crescenzi、Marco Ferrara、Jörg Habermann、Stefania Colarusso、Maria del Rosario Rico Ferreira、Ian Stansfield、Angela Claire Mackay、Immacolata Conte、Caterina Ercolani、Simone Zaramella、Maria-Cecilia Palumbi、Philip Meuleman、Geert Leroux-Roels、Claudio Giuliano、Fabrizio Fiore、Stefania Di Marco、Paola Baiocco、Uwe Koch、Giovanni Migliaccio、Sergio Altamura、Ralph Laufer、Raffaele De Francesco、Michael Rowley

  DOI：10.1021/jm1013105

  日期：2011.1.13

  Infections caused by hepatitis C virus (HCV) are a significant world health problem for which novel therapies are in urgent demand. The polymerase of HCV is responsible for the replication of viral genome and has been a prime target for drug discovery efforts. Here, we report on the further development of tetracyclic indole inhibitors, binding to an allosteric site on the thumb domain. Structure-activity relationship (SAR) studies around an indolo-benzoxazocine scaffold led to the identification of compound 33 (MK-3281), an inhibitor with good potency in the HCV subgenomic replication assay and attractive molecular properties suitable for a clinical candidate. The compound caused a consistent decrease in viremia in vivo using the chimeric mouse model of HCV infection.