1-[[2-[(2S,4R)-1-[(2S)-2-(tert-butoxycarbonylamino)-3-methyl-butanoyl]-4-[(7-methoxy-2-phenyl-4-quinolyl)oxy]pyrrolidin-2-yl]acetyl]amino]cyclopropanecarboxylic acid | 1040233-68-8

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 肽模拟物
• 英文名称: 1-[[2-[(2S,4R)-1-[(2S)-2-(tert-butoxycarbonylamino)-3-methyl-butanoyl]-4-[(7-methoxy-2-phenyl-4-quinolyl)oxy]pyrrolidin-2-yl]acetyl]amino]cyclopropanecarboxylic acid
• 英文别名: 1-[[2-[(2S,4R)-4-(7-methoxy-2-phenylquinolin-4-yl)oxy-1-[(2S)-3-methyl-2-[(2-methylpropan-2-yl)oxycarbonylamino]butanoyl]pyrrolidin-2-yl]acetyl]amino]cyclopropane-1-carboxylic acid
• CAS: 1040233-68-8
• 化学式: C₃₆H₄₄N₄O₈
• 分子量: 660.767
• InChiKey: WSXCDSDUNJEQRQ-QXTPGCHQSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.8
• 重原子数：
  48
• 可旋转键数：
  13
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.47
• 拓扑面积：
  156
• 氢给体数：
  3
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  苯磺酰胺 、 1-[[2-[(2S,4R)-1-[(2S)-2-(tert-butoxycarbonylamino)-3-methyl-butanoyl]-4-[(7-methoxy-2-phenyl-4-quinolyl)oxy]pyrrolidin-2-yl]acetyl]amino]cyclopropanecarboxylic acid 在 1,8-二氮杂双环[5.4.0]十一碳-7-烯 4-二甲氨基吡啶 、 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 N,N-二甲基甲酰胺 为溶剂， 生成 tert-butyl N-[(1S)-1-[(2S,4R)-2-[2-[[1-(benzenesulfonylcarbamoyl)cyclopropyl]amino]-2-oxo-ethyl]-4-[(7-methoxy-2-phenyl-4-quinolyl)oxy]pyrrolidine-1-carbonyl]-2-methyl-propyl]carbamate
  参考文献：
  名称：

  β-Amino acid substitutions and structure-based CoMFA modeling of hepatitis C virus NS3 protease inhibitors

  摘要：

  In an effort to develop a new type of HCV NS3 peptidomimetic inhibitor, a series of tripeptide inhibitors incorporating a mix of alpha- and beta-amino acids has been synthesized. To understand the structural implications of beta-amino acid substitution, the P-1, P-2, and P-3 positions of a potent tripeptide scaffold were scanned and combined with carboxylic acid and acyl sulfonamide C-terminal groups. Inhibition was evaluated and revealed that the structural changes resulted in a loss in potency compared with the a- peptide analogues. However, several compounds exhibited mu M potency. Inhibition data were compared with modeled ligand-protein binding poses to understand how changes in ligand structure affected inhibition potency. The P-3 position seemed to be the least sensitive position for beta-amino acid substitution. Moreover, the importance of a proper oxyanion hole interaction for good potency was suggested by both inhibition data and molecular modeling. To gain further insight into the structural requirements for potent inhibitors, a three-dimensional quantitative structure-activity relationship (3D- QSAR) model has been constructed using comparative molecular field analysis (CoMFA). The most predictive CoMFA model has q(2) = 0.48 and r(pred)(2) = 0.68. (C) 2008 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2008.04.005
• 作为产物：
  描述：

  methyl 1-(2-((2S,4R)-1-((tert-butoxycarbonyl)-L-valyl)-4-((7-methoxy-2-phenylquinolin-4-yl)oxy)pyrrolidin-2-yl)acetamido)cyclopropane-1-carboxylate 在 lithium hydroxide 作用下， 以 四氢呋喃 、 甲醇 、 水 为溶剂， 反应 4.0h， 生成 1-[[2-[(2S,4R)-1-[(2S)-2-(tert-butoxycarbonylamino)-3-methyl-butanoyl]-4-[(7-methoxy-2-phenyl-4-quinolyl)oxy]pyrrolidin-2-yl]acetyl]amino]cyclopropanecarboxylic acid
  参考文献：
  名称：

  β-Amino acid substitutions and structure-based CoMFA modeling of hepatitis C virus NS3 protease inhibitors

  摘要：

  In an effort to develop a new type of HCV NS3 peptidomimetic inhibitor, a series of tripeptide inhibitors incorporating a mix of alpha- and beta-amino acids has been synthesized. To understand the structural implications of beta-amino acid substitution, the P-1, P-2, and P-3 positions of a potent tripeptide scaffold were scanned and combined with carboxylic acid and acyl sulfonamide C-terminal groups. Inhibition was evaluated and revealed that the structural changes resulted in a loss in potency compared with the a- peptide analogues. However, several compounds exhibited mu M potency. Inhibition data were compared with modeled ligand-protein binding poses to understand how changes in ligand structure affected inhibition potency. The P-3 position seemed to be the least sensitive position for beta-amino acid substitution. Moreover, the importance of a proper oxyanion hole interaction for good potency was suggested by both inhibition data and molecular modeling. To gain further insight into the structural requirements for potent inhibitors, a three-dimensional quantitative structure-activity relationship (3D- QSAR) model has been constructed using comparative molecular field analysis (CoMFA). The most predictive CoMFA model has q(2) = 0.48 and r(pred)(2) = 0.68. (C) 2008 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2008.04.005

文献信息

• β-Amino acid substitutions and structure-based CoMFA modeling of hepatitis C virus NS3 protease inhibitors
  作者：Johanna Nurbo、Shane D. Peterson、Göran Dahl、U. Helena Danielson、Anders Karlén、Anja Sandström

  DOI：10.1016/j.bmc.2008.04.005

  日期：2008.5

  In an effort to develop a new type of HCV NS3 peptidomimetic inhibitor, a series of tripeptide inhibitors incorporating a mix of alpha- and beta-amino acids has been synthesized. To understand the structural implications of beta-amino acid substitution, the P-1, P-2, and P-3 positions of a potent tripeptide scaffold were scanned and combined with carboxylic acid and acyl sulfonamide C-terminal groups. Inhibition was evaluated and revealed that the structural changes resulted in a loss in potency compared with the a- peptide analogues. However, several compounds exhibited mu M potency. Inhibition data were compared with modeled ligand-protein binding poses to understand how changes in ligand structure affected inhibition potency. The P-3 position seemed to be the least sensitive position for beta-amino acid substitution. Moreover, the importance of a proper oxyanion hole interaction for good potency was suggested by both inhibition data and molecular modeling. To gain further insight into the structural requirements for potent inhibitors, a three-dimensional quantitative structure-activity relationship (3D- QSAR) model has been constructed using comparative molecular field analysis (CoMFA). The most predictive CoMFA model has q(2) = 0.48 and r(pred)(2) = 0.68. (C) 2008 Elsevier Ltd. All rights reserved.