(2R,6S,13aS,14aR,16aS,Z)-6-(((tert-butoxy)carbonyl)amino)-14a-((cyclopropylsulfonyl)carbamoyl)-9-methyl-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[n]pyrrolo[2,1-c][1,4,9]triazacyclopentadecin-2-yl 4-fluoroisoindoline-2-carboxylate | 1439898-53-9

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: (2R,6S,13aS,14aR,16aS,Z)-6-(((tert-butoxy)carbonyl)amino)-14a-((cyclopropylsulfonyl)carbamoyl)-9-methyl-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[n]pyrrolo[2,1-c][1,4,9]triazacyclopentadecin-2-yl 4-fluoroisoindoline-2-carboxylate
• 英文别名: [(1S,4R,6S,7Z,14S,18R)-4-(cyclopropylsulfonylcarbamoyl)-11-methyl-14-[(2-methylpropan-2-yl)oxycarbonylamino]-2,15-dioxo-3,11,16-triazatricyclo[14.3.0.04,6]nonadec-7-en-18-yl] 4-fluoro-1,3-dihydroisoindole-2-carboxylate
• CAS: 1439898-53-9
• 化学式: C₃₅H₄₇FN₆O₉S
• 分子量: 746.857
• InChiKey: CQLFBAODQHOJAW-WNFNEINCSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.9
• 重原子数：
  52
• 可旋转键数：
  8
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.63
• 拓扑面积：
  192
• 氢给体数：
  3
• 氢受体数：
  11

反应信息

• 作为产物：
  描述：

  (2R,6S,13aS,14aR,16aS,Z)-6-(((tert-butoxy)carbonyl)amino)-14a-((cyclopropylsulfonyl)carbamoyl)-9-(2-nitrophenylsulfonyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[n]pyrrolo[2,1-c][1,4,9]triazacyclopentadecin-2-yl 4-fluoroisoindoline-2-carboxylate 在 potassium carbonate 、 溶剂黄146 、 苯硫酚 作用下， 以 甲醇 、 乙腈 为溶剂， 反应 49.33h， 生成 (2R,6S,13aS,14aR,16aS,Z)-6-(((tert-butoxy)carbonyl)amino)-14a-((cyclopropylsulfonyl)carbamoyl)-9-methyl-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[n]pyrrolo[2,1-c][1,4,9]triazacyclopentadecin-2-yl 4-fluoroisoindoline-2-carboxylate
  参考文献：
  名称：

  Discovery of Danoprevir (ITMN-191/R7227), a Highly Selective and Potent Inhibitor of Hepatitis C Virus (HCV) NS3/4A Protease

  摘要：

  HCV serine protease NS3 represents an attractive drug target because it is not only essential for viral replication but also implicated in the viral evasion of the host immune response pathway through direct cleavage of key proteins in the human innate immune system. Through structure-based drug design and optimization, macrocyclic peptidomimetic molecules bearing both a lipophilic P2 isoindoline carbamate and a Pl/P1' acylsulfonamide/acylsulfamide carboxylic acid bioisostere were prepared that possessed subnanomolar potency against the NS3 protease in a subgenomic replicon-based cellular assay (Huh-7). Danoprevir (compound 49) was selected as the clinical development candidate for its favorable potency profile across multiple HCV genotypes and key mutant strains and for its good in vitro ADME profiles and in vivo target tissue (liver) exposures across multiple animal species. X-ray crystallographic studies elucidated several key features in the binding of danoprevir to HCV NS3 protease and proved invaluable to our iterative structure-based design strategy.

  DOI：

  10.1021/jm400164c

文献信息

• Discovery of Danoprevir (ITMN-191/R7227), a Highly Selective and Potent Inhibitor of Hepatitis C Virus (HCV) NS3/4A Protease
  作者：Yutong Jiang、Steven W. Andrews、Kevin R. Condroski、Brad Buckman、Vlad Serebryany、Steve Wenglowsky、April L. Kennedy、Machender R. Madduru、Bin Wang、Michael Lyon、George A. Doherty、Benjamin T. Woodard、Christine Lemieux、Mary Geck Do、Hailong Zhang、Joshua Ballard、Guy Vigers、Barbra J. Brandhuber、Peter Stengel、John A. Josey、Leonid Beigelman、Lawrence Blatt、Scott D. Seiwert

  DOI：10.1021/jm400164c

  日期：2014.3.13

  HCV serine protease NS3 represents an attractive drug target because it is not only essential for viral replication but also implicated in the viral evasion of the host immune response pathway through direct cleavage of key proteins in the human innate immune system. Through structure-based drug design and optimization, macrocyclic peptidomimetic molecules bearing both a lipophilic P2 isoindoline carbamate and a Pl/P1' acylsulfonamide/acylsulfamide carboxylic acid bioisostere were prepared that possessed subnanomolar potency against the NS3 protease in a subgenomic replicon-based cellular assay (Huh-7). Danoprevir (compound 49) was selected as the clinical development candidate for its favorable potency profile across multiple HCV genotypes and key mutant strains and for its good in vitro ADME profiles and in vivo target tissue (liver) exposures across multiple animal species. X-ray crystallographic studies elucidated several key features in the binding of danoprevir to HCV NS3 protease and proved invaluable to our iterative structure-based design strategy.