methyl 1-((2S,4R)-1-((R)-3-((tert-butoxycarbonyl)amino)-4-methylpentanoyl)-4-((7-methoxy-2-phenylquinolin-4-yl)oxy)pyrrolidine-2-carboxamido)cyclopropane-1-carboxylate | 1040233-62-2

• 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: methyl 1-((2S,4R)-1-((R)-3-((tert-butoxycarbonyl)amino)-4-methylpentanoyl)-4-((7-methoxy-2-phenylquinolin-4-yl)oxy)pyrrolidine-2-carboxamido)cyclopropane-1-carboxylate
• CAS: 1040233-62-2
• 化学式: C₃₇H₄₆N₄O₈
• 分子量: 674.794
• InChiKey: OUIKBKJLHBXBDB-AHKAMDFCSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.02
• 重原子数：
  49.0
• 可旋转键数：
  11.0
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.49
• 拓扑面积：
  145.39
• 氢给体数：
  2.0
• 氢受体数：
  9.0

反应信息

• 作为反应物：
  描述：

  methyl 1-((2S,4R)-1-((R)-3-((tert-butoxycarbonyl)amino)-4-methylpentanoyl)-4-((7-methoxy-2-phenylquinolin-4-yl)oxy)pyrrolidine-2-carboxamido)cyclopropane-1-carboxylate 在 lithium hydroxide 作用下， 以 四氢呋喃 、 甲醇 、 水 为溶剂， 反应 5.0h， 以96%的产率得到1-[[(2S,4R)-1-[(3R)-3-(tert-butoxycarbonylamino)-4-methyl-pentanoyl]-4-[(7-methoxy-2-phenyl-4-quinolyl)oxy]pyrrolidine-2-carbonyl]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
• 作为产物：
  描述：

  (2S,4R)-1-((R)-3-((tert-butoxycarbonyl)amino)-4-methylpentanoyl)-4-((7-methoxy-2-phenylquinolin-4-yl)oxy)pyrrolidine-2-carboxylic acid 、 1-氨基环丙烷甲酸甲酯盐酸盐 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 4.0h， 以76%的产率得到methyl 1-((2S,4R)-1-((R)-3-((tert-butoxycarbonyl)amino)-4-methylpentanoyl)-4-((7-methoxy-2-phenylquinolin-4-yl)oxy)pyrrolidine-2-carboxamido)cyclopropane-1-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