methyl (2S,4R)-1-((R)-3-((tert-butoxycarbonyl)amino)-4-methylpentanoyl)-4-((7-methoxy-2-phenylquinolin-4-yl)oxy)pyrrolidine-2-carboxylate | 1040233-47-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 喹啉及其衍生物
• 英文名称: methyl (2S,4R)-1-((R)-3-((tert-butoxycarbonyl)amino)-4-methylpentanoyl)-4-((7-methoxy-2-phenylquinolin-4-yl)oxy)pyrrolidine-2-carboxylate
• CAS: 1040233-47-3
• 化学式: C₃₃H₄₁N₃O₇
• 分子量: 591.704
• InChiKey: ZOLXYPJDKGXRRR-LOLUNWTRSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.37
• 重原子数：
  43.0
• 可旋转键数：
  9.0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.45
• 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：

  methyl (2S,4R)-1-((R)-3-((tert-butoxycarbonyl)amino)-4-methylpentanoyl)-4-((7-methoxy-2-phenylquinolin-4-yl)oxy)pyrrolidine-2-carboxylate 在 lithium hydroxide 作用下， 以 四氢呋喃 、 甲醇 、 水 为溶剂， 反应 2.5h， 以97%的产率得到(2S,4R)-1-((R)-3-((tert-butoxycarbonyl)amino)-4-methylpentanoyl)-4-((7-methoxy-2-phenylquinolin-4-yl)oxy)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：

  [(2S,4R)-4-(7-methoxy-2-phenylquinolin-4-yloxy)pyrrolidin-2-yl]carboxylic acid dihydrochloride 、 叔丁氧羰基-β-亮氨酸 在 O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate 、 N,N-二异丙基乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 3.0h， 以87%的产率得到methyl (2S,4R)-1-((R)-3-((tert-butoxycarbonyl)amino)-4-methylpentanoyl)-4-((7-methoxy-2-phenylquinolin-4-yl)oxy)pyrrolidine-2-carboxylate
  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