26-Cyclohexyl-20-methoxy-10,14-dimethyl-9,9-dioxo-9lambda6-thia-1,8,10,14-tetrazapentacyclo[14.8.1.12,6.13,24.018,23]heptacosa-2,4,6(27),16,18(23),19,21,24(26)-octaene-7,15-dione | 1384258-94-9

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 大环内酰胺类
• 英文名称: 26-Cyclohexyl-20-methoxy-10,14-dimethyl-9,9-dioxo-9lambda6-thia-1,8,10,14-tetrazapentacyclo[14.8.1.12,6.13,24.018,23]heptacosa-2,4,6(27),16,18(23),19,21,24(26)-octaene-7,15-dione
• 英文别名: 26-cyclohexyl-20-methoxy-10,14-dimethyl-9,9-dioxo-9λ6-thia-1,8,10,14-tetrazapentacyclo[14.8.1.12,6.13,24.018,23]heptacosa-2,4,6(27),16,18(23),19,21,24(26)-octaene-7,15-dione
• CAS: 1384258-94-9
• 化学式: C₃₁H₃₆N₄O₅S
• 分子量: 576.717
• InChiKey: KTHHACXJWUSTDW-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.7
• 重原子数：
  41
• 可旋转键数：
  2
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.42
• 拓扑面积：
  109
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  3-环己基-2-(2-甲酰基-4-甲氧基苯基)-1H-吲哚-6-羧酸1,1-二甲基乙基酯 在 sulfonamide 、 水 、 caesium carbonate 、 O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate 、 1,8-二氮杂双环[5.4.0]十一碳-7-烯 、 N,N-二异丙基乙胺 、 三氟乙酸 、 lithium hydroxide 作用下， 以 四氢呋喃 、 二恶烷 、 甲醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 生成 26-Cyclohexyl-20-methoxy-10,14-dimethyl-9,9-dioxo-9lambda6-thia-1,8,10,14-tetrazapentacyclo[14.8.1.12,6.13,24.018,23]heptacosa-2,4,6(27),16,18(23),19,21,24(26)-octaene-7,15-dione
  参考文献：
  名称：

  Finger loop inhibitors of the HCV NS5b polymerase. Part II. Optimization of tetracyclic indole-based macrocycle leading to the discovery of TMC647055

  摘要：

  Optimization of a novel series of macrocyclic indole-based inhibitors of the HCV NS5b polymerase targeting the finger loop domain led to the discovery of lead compounds exhibiting improved potency in cellular assays and superior pharmacokinetic profile. Further lead optimization performed on the most promising unsaturated-bridged subseries provided the clinical candidate 27-cyclohexyl-12,13,16,17-tetrahydro-22-methoxy-11,17-dimethyl-10,10-dioxide-2,19-methano-3,7: 4,1-dimetheno-1H, 11H-14,10,2,9,11,17-benzoxathiatetraazacyclo docosine-8,18(9H, 15H)-dione, TMC647055 (compound 18a). This non-zwitterionic 17-membered ring macrocycle combines nanomolar cellular potency (EC50 of 82 nM) with minimal associated cell toxicity (CC50 >20 mu M) and promising pharmacokinetic profiles in rats and dogs. TMC647055 is currently being evaluated in the clinic. (C) 2012 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2012.04.113

文献信息

• Finger loop inhibitors of the HCV NS5b polymerase. Part II. Optimization of tetracyclic indole-based macrocycle leading to the discovery of TMC647055
  作者：Sandrine Vendeville、Tse-I. Lin、Lili Hu、Abdellah Tahri、David McGowan、Maxwell D. Cummings、Katie Amssoms、Maxime Canard、Stefaan Last、Iris Van den Steen、Benoit Devogelaere、Marie-Claude Rouan、Leen Vijgen、Jan Martin Berke、Pascale Dehertogh、Els Fransen、Erna Cleiren、Liesbet van der Helm、Gregory Fanning、Kristof Van Emelen、Origène Nyanguile、Kenny Simmen、Pierre Raboisson

  DOI：10.1016/j.bmcl.2012.04.113

  日期：2012.7

  Optimization of a novel series of macrocyclic indole-based inhibitors of the HCV NS5b polymerase targeting the finger loop domain led to the discovery of lead compounds exhibiting improved potency in cellular assays and superior pharmacokinetic profile. Further lead optimization performed on the most promising unsaturated-bridged subseries provided the clinical candidate 27-cyclohexyl-12,13,16,17-tetrahydro-22-methoxy-11,17-dimethyl-10,10-dioxide-2,19-methano-3,7: 4,1-dimetheno-1H, 11H-14,10,2,9,11,17-benzoxathiatetraazacyclo docosine-8,18(9H, 15H)-dione, TMC647055 (compound 18a). This non-zwitterionic 17-membered ring macrocycle combines nanomolar cellular potency (EC50 of 82 nM) with minimal associated cell toxicity (CC50 >20 mu M) and promising pharmacokinetic profiles in rats and dogs. TMC647055 is currently being evaluated in the clinic. (C) 2012 Elsevier Ltd. All rights reserved.