methyl (2S,4R)-1-[(2S)-2-(cyclopentyloxycarbonylamino)-3,3-dimethylbutanoyl]-4-(7-methoxy-2-phenylquinolin-4-yl)oxypyrrolidine-2-carboxylate | 877068-88-7

• 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 (2S,4R)-1-[(2S)-2-(cyclopentyloxycarbonylamino)-3,3-dimethylbutanoyl]-4-(7-methoxy-2-phenylquinolin-4-yl)oxypyrrolidine-2-carboxylate
• CAS: 877068-88-7
• 化学式: C₃₄H₄₁N₃O₇
• 分子量: 603.715
• InChiKey: XYHMVOXWGFVENS-SHFQUTHWSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.2
• 重原子数：
  44
• 可旋转键数：
  11
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.47
• 拓扑面积：
  116
• 氢给体数：
  1
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  methyl (2S,4R)-1-[(2S)-2-(cyclopentyloxycarbonylamino)-3,3-dimethylbutanoyl]-4-(7-methoxy-2-phenylquinolin-4-yl)oxypyrrolidine-2-carboxylate 在 lithium hydroxide 作用下， 以 四氢呋喃 为溶剂， 生成 (1R,2S)-1-[[(2S,4R)-1-[(2S)-2-(cyclopentyloxycarbonylamino)-3,3-dimethylbutanoyl]-4-(7-methoxy-2-phenylquinolin-4-yl)oxypyrrolidine-2-carbonyl]amino]-2-ethenylcyclopropane-1-carboxylic acid
  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
• 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 methyl (2S,4R)-1-[(2S)-2-(cyclopentyloxycarbonylamino)-3,3-dimethylbutanoyl]-4-(7-methoxy-2-phenylquinolin-4-yl)oxypyrrolidine-2-carboxylate
  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

• ANTIVIRAL PHOSPHINATE COMPOUNDS
  申请人：Casarez Anthony

  公开号：US20090227491A1

  公开（公告）日：2009-09-10

  The invention is related to anti-viral phosphinate compounds, compositions containing such compounds, and therapeutic methods that include the administration of such compounds, as well as to processes and intermediates useful for preparing such compounds.

  该发明涉及抗病毒磷酸酯化合物，含有这些化合物的组合物，以及包括给予这些化合物的治疗方法，还涉及用于制备这些化合物的过程和中间体。
• Antiviral phosphinate compounds
  申请人：Casarez Anthony

  公开号：US20080057031A1

  公开（公告）日：2008-03-06

  The invention is related to anti-viral phosphinate compounds, compositions containing such compounds, and therapeutic methods that include the administration of such compounds, as well as to processes and intermediates useful for preparing such compounds.

  本发明涉及抗病毒膦酸酯化合物、含有此类化合物的组合物、包括该类化合物的给药治疗方法，以及用于制备此类化合物的过程和中间体。
• Antiviral Compounds
  申请人：Chaudhary Kleem

  公开号：US20080311077A1

  公开（公告）日：2008-12-18

  The invention is related to phosphorus substituted anti-viral inhibitory compounds, compositions containing such compounds, and therapeutic methods that include the administration of such compounds, as well as to processes and intermediates useful for preparing such compounds.

  该发明涉及磷取代的抗病毒抑制化合物，含有这种化合物的组合物和包括该化合物的治疗方法，以及用于制备这种化合物的过程和中间体。
• Antiviral compounds
  申请人：GILEAD SCIENCES, INC.

  公开号：EP2316839A1

  公开（公告）日：2011-05-04

  The invention is related to phosphorus substituted anti-viral inhibitory compounds, compositions containing such compounds, and therapeutic methods that include the administration of such compounds, as well as to processes and intermediates useful for preparing such compounds.

  本发明涉及磷取代的抗病毒抑制化合物、含有此类化合物的组合物、包括施用此类化合物的治疗方法，以及制备此类化合物的工艺和中间体。
• [EN] ANTIVIRAL COMPOUNDS<br/>[FR] COMPOSÉS ANTIVIRAUX
  申请人：GILEAD SCIENCES INC

  公开号：WO2006020276A3

  公开（公告）日：2006-10-05