(2S,4R)-methyl 1-((S)-2-((3,3-dimethylhex-5-enyloxy)carbonylamino)-3,3-dimethylbutanoyl)-4-methoxy-4-(6-methoxy-7-vinylnaphthalen-2-yl)pyrrolidine-2-carboxylate

• 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: (2S,4R)-methyl 1-((S)-2-((3,3-dimethylhex-5-enyloxy)carbonylamino)-3,3-dimethylbutanoyl)-4-methoxy-4-(6-methoxy-7-vinylnaphthalen-2-yl)pyrrolidine-2-carboxylate
• 英文别名: methyl (2S,4R)-1-[(2S)-2-(3,3-dimethylhex-5-enoxycarbonylamino)-3,3-dimethylbutanoyl]-4-(7-ethenyl-6-methoxynaphthalen-2-yl)-4-methoxypyrrolidine-2-carboxylate
• 化学式: C₃₅H₄₈N₂O₇
• 分子量: 608.775
• InChiKey: BFVYRHZOXKNIDJ-AETKFNHJSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  7.2
• 重原子数：
  44
• 可旋转键数：
  15
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.51
• 拓扑面积：
  103
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  (2S,4R)-methyl 1-((S)-2-((3,3-dimethylhex-5-enyloxy)carbonylamino)-3,3-dimethylbutanoyl)-4-methoxy-4-(6-methoxy-7-vinylnaphthalen-2-yl)pyrrolidine-2-carboxylate 在 RuCl2(1,3-dimesityl-imidazolidin-2-yl)(PCy3)(=CHPh) 、 palladium on activated charcoal 、 氢气 、 N,N-二异丙基乙胺 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 、 lithium hydroxide 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 乙酸乙酯 、 1,2-二氯乙烷 为溶剂， 反应 4.0h， 生成 (2R,4S,7S)-7-tert-butyl-N-[(1R,2S)-2-cyclopropyl-1-(cyclopropylsulfonylcarbamoyl)cyclopropyl]-2,18-dimethoxy-13,13-dimethyl-6,9-dioxo-10-oxa-5,8-diazatetracyclo[15.5.3.12,5.020,24]hexacosa-1(23),17,19,21,24-pentaene-4-carboxamide
  参考文献：
  名称：

  The discovery and optimization of naphthalene-linked P2-P4 Macrocycles as inhibitors of HCV NS3 protease

  摘要：

  Naphthalene-linked P2-P4 macrocycles within a tri-peptide-based acyl sulfonamide chemotype have been synthesized and found to inhibit HCV NS3 proteases representing genotypes 1a and 1b with single digit nanomolar potency. The pharmacokinetic profile of compounds in this series was optimized through structural modifications along the macrocycle tether as well as the P1 subsite. Ultimately a compound with oral bioavailability of 100% in rat, and a long half-life in plasma was obtained. However, compounds in this macrocyclic series exhibited cardiac effects in an isolated rabbit heart model and for this reason further optimization efforts were discontinued. (C) 2017 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2017.11.005
• 作为产物：
  描述：

  ethyl 3,3-dimethyl-5-hexenoate 在 lithium aluminium tetrahydride 、 三光气 、 N,N-二异丙基乙胺 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 作用下， 以 1,4-二氧六环 、 乙醚 、 二氯甲烷 为溶剂， 反应 5.08h， 生成 (2S,4R)-methyl 1-((S)-2-((3,3-dimethylhex-5-enyloxy)carbonylamino)-3,3-dimethylbutanoyl)-4-methoxy-4-(6-methoxy-7-vinylnaphthalen-2-yl)pyrrolidine-2-carboxylate
  参考文献：
  名称：

  The discovery and optimization of naphthalene-linked P2-P4 Macrocycles as inhibitors of HCV NS3 protease

  摘要：

  Naphthalene-linked P2-P4 macrocycles within a tri-peptide-based acyl sulfonamide chemotype have been synthesized and found to inhibit HCV NS3 proteases representing genotypes 1a and 1b with single digit nanomolar potency. The pharmacokinetic profile of compounds in this series was optimized through structural modifications along the macrocycle tether as well as the P1 subsite. Ultimately a compound with oral bioavailability of 100% in rat, and a long half-life in plasma was obtained. However, compounds in this macrocyclic series exhibited cardiac effects in an isolated rabbit heart model and for this reason further optimization efforts were discontinued. (C) 2017 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2017.11.005

文献信息

• Hepatitis C Virus Inhibitors
  申请人：Hiebert Sheldon

  公开号：US20100080770A1

  公开（公告）日：2010-04-01

  Hepatitis C virus inhibitors having the general formula are disclosed. Compositions comprising the compounds and methods for using the compounds to inhibit HCV are also disclosed.

  揭示了具有一般式的丙型肝炎病毒抑制剂。还揭示了包含这些化合物的组合物以及使用这些化合物抑制HCV的方法。
• HEPATITIS C VIRUS INHIBITORS
  申请人：Bristol-Myers Squibb Company

  公开号：EP2331552B1

  公开（公告）日：2013-02-27
• The discovery and optimization of naphthalene-linked P2-P4 Macrocycles as inhibitors of HCV NS3 protease
  作者：Michael Bowsher、Sheldon Hiebert、Rongti Li、Alan X. Wang、Jacques Friborg、Fei Yu、Dennis Hernandez、Ying-Kai Wang、Herbert Klei、Ramkumar Rajamani、Kathy Mosure、Jay O. Knipe、Nicholas A. Meanwell、Fiona McPhee、Paul M. Scola

  DOI：10.1016/j.bmcl.2017.11.005

  日期：2018.1

  Naphthalene-linked P2-P4 macrocycles within a tri-peptide-based acyl sulfonamide chemotype have been synthesized and found to inhibit HCV NS3 proteases representing genotypes 1a and 1b with single digit nanomolar potency. The pharmacokinetic profile of compounds in this series was optimized through structural modifications along the macrocycle tether as well as the P1 subsite. Ultimately a compound with oral bioavailability of 100% in rat, and a long half-life in plasma was obtained. However, compounds in this macrocyclic series exhibited cardiac effects in an isolated rabbit heart model and for this reason further optimization efforts were discontinued. (C) 2017 Elsevier Ltd. All rights reserved.