| 445306-52-5

• 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
• CAS: 445306-52-5
• 化学式: C₃₂H₃₉N₃O₇
• 分子量: 577.678
• InChiKey: STZTVHPWCYAYEU-ZEZZXZOMSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.98
• 重原子数：
  42.0
• 可旋转键数：
  8.0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.44
• 拓扑面积：
  116.29
• 氢给体数：
  1.0
• 氢受体数：
  8.0

反应信息

• 作为反应物：
  描述：

  在 lithium hydroxide 作用下， 以 四氢呋喃 、 甲醇 、 水 为溶剂， 反应 2.0h， 以94%的产率得到(2S,4R)-4-(7-methoxy-2-phenylquinolin-4-yl)oxy-1-[(2S)-3-methyl-2-[(2-methylpropan-2-yl)oxycarbonylamino]butanoyl]pyrrolidine-2-carboxylic 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
• 作为产物：
  描述：

  N-Boc-顺式-4-羟基-L-脯氨酸甲酯 在 盐酸 、 O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate 、 三苯基膦 、 偶氮二甲酸二乙酯 作用下， 以 1,4-二氧六环 为溶剂， 生成
  参考文献：
  名称：

  A Systematic Approach to the Optimization of Substrate-Based Inhibitors of the Hepatitis C Virus NS3 Protease:  Discovery of Potent and Specific Tripeptide Inhibitors

  摘要：

  The inadequate efficacy and tolerability of current therapies for the infectious liver disease caused by the hepatitis C virus have warranted significant efforts in the development of new therapeutics. We have previously reported competitive peptide inhibitors of the NS3 serine protease based on the N-terminal cleavage products of peptide substrates. A detailed study of the interactions of these substrate-based inhibitors with the different subsites of the serine protease active site led to the discovery of novel residues that increased the affinity of the inhibitors. In this paper, we report the combination of the best binding residues in a tetrapeptide series that resulted in extremely potent inhibitors that bind exquisitely well to this enzyme. A substantial increase in potency was obtained with the simultaneous introduction of a 7-methoxy-2-phenyl-4-quinolinoxy moiety at the gamma-position of the P2 proline and a tert-leucine as a P3 residue. The increase in potency allowed for the further truncation and led to the identification of tripeptide inhibitors. Structure activity relationship studies on this inhibitor series led to the identification of carbamate-containing tripeptides that are able to inhibit replication of subgenomic HCV RNA in cell culture with potencies below 1 muM. This inhibitor series has the potential of becoming antiviral agents for the treatment of HCV infections.

  DOI：

  10.1021/jm0494523

文献信息

• A Systematic Approach to the Optimization of Substrate-Based Inhibitors of the Hepatitis C Virus NS3 Protease:  Discovery of Potent and Specific Tripeptide Inhibitors
  作者：Montse Llinàs-Brunet、Murray D. Bailey、Elise Ghiro、Vida Gorys、Ted Halmos、Martin Poirier、Jean Rancourt、Nathalie Goudreau

  DOI：10.1021/jm0494523

  日期：2004.12.1

  The inadequate efficacy and tolerability of current therapies for the infectious liver disease caused by the hepatitis C virus have warranted significant efforts in the development of new therapeutics. We have previously reported competitive peptide inhibitors of the NS3 serine protease based on the N-terminal cleavage products of peptide substrates. A detailed study of the interactions of these substrate-based inhibitors with the different subsites of the serine protease active site led to the discovery of novel residues that increased the affinity of the inhibitors. In this paper, we report the combination of the best binding residues in a tetrapeptide series that resulted in extremely potent inhibitors that bind exquisitely well to this enzyme. A substantial increase in potency was obtained with the simultaneous introduction of a 7-methoxy-2-phenyl-4-quinolinoxy moiety at the gamma-position of the P2 proline and a tert-leucine as a P3 residue. The increase in potency allowed for the further truncation and led to the identification of tripeptide inhibitors. Structure activity relationship studies on this inhibitor series led to the identification of carbamate-containing tripeptides that are able to inhibit replication of subgenomic HCV RNA in cell culture with potencies below 1 muM. This inhibitor series has the potential of becoming antiviral agents for the treatment of HCV infections.
• 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.