ethyl 3-methyl-N-[(pent-4-en-1-yloxy)carbonyl]-L-valyl-(4R)-4-[(7-bromoisoquinolin-1-yl)oxy]-L-prolinate | 924271-73-8

• 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: ethyl 3-methyl-N-[(pent-4-en-1-yloxy)carbonyl]-L-valyl-(4R)-4-[(7-bromoisoquinolin-1-yl)oxy]-L-prolinate
• 英文别名: ethyl (2S,4R)-4-(7-bromoisoquinolin-1-yl)oxy-1-[(2S)-3,3-dimethyl-2-(pent-4-enoxycarbonylamino)butanoyl]pyrrolidine-2-carboxylate
• CAS: 924271-73-8
• 化学式: C₂₈H₃₆BrN₃O₆
• 分子量: 590.514
• InChiKey: FZPYGSILLVSPKM-AKIFATBCSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.1
• 重原子数：
  38
• 可旋转键数：
  13
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  107
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  ethyl 3-methyl-N-[(pent-4-en-1-yloxy)carbonyl]-L-valyl-(4R)-4-[(7-bromoisoquinolin-1-yl)oxy]-L-prolinate 在 乙醇 、 N,N-二异丙基乙胺 、 Methanaminium,N-[(dimethylamino)(3H-1,2,3-triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methyl-, hexafluorophosphate(1-) 、 lithium hydroxide 作用下， 以 四氢呋喃 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 生成 C₃₅H₄₃N₅O₈S
  参考文献：
  名称：

  Discovery of MK-1220: A Macrocyclic Inhibitor of Hepatitis C Virus NS3/4A Protease with Improved Preclinical Plasma Exposure

  摘要：

  The discovery of MK-1220 is reported along with the development of a series of HCV NS3/4A protease inhibitors containing a P2 to P4 macrocyclic constraint with improved preclinical pharmacokinetics. Optimization of the P2 heterocycle substitution pattern as well as the P3 amino acid led to compounds with greatly improved plasma exposure following oral dosing in both rats and dogs while maintaining excellent enzyme potency and cellular activity. These studies led to the identification of MK-1220.

  DOI：

  10.1021/ml1002426
• 作为产物：
  描述：

  3-methyl-N-[(pent-4-en-1-yloxy)carbonyl]-L-valine 、 C₁₆H₁₇BrN₂O₃ 在 N,N-二异丙基乙胺 、 Methanaminium,N-[(dimethylamino)(3H-1,2,3-triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methyl-, hexafluorophosphate(1-) 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 生成 ethyl 3-methyl-N-[(pent-4-en-1-yloxy)carbonyl]-L-valyl-(4R)-4-[(7-bromoisoquinolin-1-yl)oxy]-L-prolinate
  参考文献：
  名称：

  Discovery of MK-1220: A Macrocyclic Inhibitor of Hepatitis C Virus NS3/4A Protease with Improved Preclinical Plasma Exposure

  摘要：

  The discovery of MK-1220 is reported along with the development of a series of HCV NS3/4A protease inhibitors containing a P2 to P4 macrocyclic constraint with improved preclinical pharmacokinetics. Optimization of the P2 heterocycle substitution pattern as well as the P3 amino acid led to compounds with greatly improved plasma exposure following oral dosing in both rats and dogs while maintaining excellent enzyme potency and cellular activity. These studies led to the identification of MK-1220.

  DOI：

  10.1021/ml1002426

文献信息

• HCV NS3 Protease Inhibitors
  申请人：Holloway M. Katharine

  公开号：US20110028494A1

  公开（公告）日：2011-02-03

  The present invention relates to macrocyclic compounds of formula (I) that are useful as inhibitors of the hepatitis C virus (HCV) NS3 protease, their synthesis, and their use for treating or preventing HCV infections.

  本发明涉及公式（I）的大环化合物，其可用作丙型肝炎病毒（HCV）NS3蛋白酶的抑制剂，其合成以及其用于治疗或预防HCV感染的用途。
• Molecular Modeling Based Approach to Potent P2−P4 Macrocyclic Inhibitors of Hepatitis C NS3/4A Protease
  作者：Nigel J. Liverton、M. Katharine Holloway、John A. McCauley、Michael T. Rudd、John W. Butcher、Steven S. Carroll、Jillian DiMuzio、Christine Fandozzi、Kevin F. Gilbert、Shi-Shan Mao、Charles J. McIntyre、Kevin T. Nguyen、Joseph J. Romano、Mark Stahlhut、Bang-Lin Wan、David B. Olsen、Joseph P. Vacca

  DOI：10.1021/ja711120r

  日期：2008.4.1

  Molecular modeling of inhibitor bound full length HCV NS3/4A protease structures proved to be a valuable tool in the design of a new series of potent NS3 protease inhibitors. Optimization of initial compounds provided 25a. The in vitro activity and selectivity as well as the rat pharmacokinetic profile of 25a compare favorably with the data for other NS3/4A protease inhibitors currently in clinical development for the treatment of HCV.
• US8278322B2
  申请人：——

  公开号：US8278322B2

  公开（公告）日：2012-10-02
• Discovery of MK-1220: A Macrocyclic Inhibitor of Hepatitis C Virus NS3/4A Protease with Improved Preclinical Plasma Exposure
  作者：Michael T. Rudd、John A. McCauley、John W. Butcher、Joseph J. Romano、Charles J. McIntyre、Kevin T. Nguyen、Kevin F. Gilbert、Kimberly J. Bush、M. Katharine Holloway、John Swestock、Bang-Lin Wan、Steven S. Carroll、Jillian M. DiMuzio、Donald J. Graham、Steven W. Ludmerer、Mark W. Stahlhut、Christine M. Fandozzi、Nicole Trainor、David B. Olsen、Joseph P. Vacca、Nigel J. Liverton

  DOI：10.1021/ml1002426

  日期：2011.3.10

  The discovery of MK-1220 is reported along with the development of a series of HCV NS3/4A protease inhibitors containing a P2 to P4 macrocyclic constraint with improved preclinical pharmacokinetics. Optimization of the P2 heterocycle substitution pattern as well as the P3 amino acid led to compounds with greatly improved plasma exposure following oral dosing in both rats and dogs while maintaining excellent enzyme potency and cellular activity. These studies led to the identification of MK-1220.