(2R,5S,7S)-1-aza-7-benzyloxycarbonylamino-8-oxo-4-thiabicyclo[3.3.0]octane-2-carbonitrile | 1193377-39-7

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: (2R,5S,7S)-1-aza-7-benzyloxycarbonylamino-8-oxo-4-thiabicyclo[3.3.0]octane-2-carbonitrile
• 英文别名: benzyl N-[(3R,6S,7aS)-3-cyano-5-oxo-3,6,7,7a-tetrahydro-2H-pyrrolo[2,1-b][1,3]thiazol-6-yl]carbamate
• CAS: 1193377-39-7
• 化学式: C₁₅H₁₅N₃O₃S
• 分子量: 317.368
• InChiKey: WNQAJNNTYHSICO-AGIUHOORSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.5
• 重原子数：
  22
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  108
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (2R,5S,7S)-1-aza-7-benzyloxycarbonylamino-8-oxo-4-thiabicyclo[3.3.0]octane-2-carbonitrile 在 ammonium peroxydisulfate 作用下， 以 四氢呋喃 、 水 为溶剂， 反应 16.0h， 生成 、 、 、 、 、
  参考文献：
  名称：

  基于氰基噻唑烷的脯氨酰寡肽酶抑制剂的代谢不稳定性：结构分配挑战和潜在的药物化学意义。

  摘要：

  作为基于氰基噻唑烷的脯氨酰寡肽酶抑制剂开发的一部分，初步代谢研究表明P450酶可氧化多个位点。令人惊讶的是，深入的研究表明，在多个立体遗传学中心的差向异构是将单一主要代谢物转化为一系列次要代谢物的原因。所有七个检测到的分子的快速异构化都无法使用NMR光谱法或X射线晶体学进行完整的结构测定，从而提出了有趣的结构阐明挑战。通过结合LC-MS分析，合成工作，氘交换研究和计算预测，我们能够表征所有代谢物并阐明其在溶液中的动态行为。在药物开发的背景下，

  DOI：

  10.1002/cmdc.201500114
• 作为产物：
  描述：

  (2R,5S,7S)-1-aza-7-benzyloxycarbonylamino-8-oxo-4-thiabicyclo[3.3.0]octane-2-carboxamide 在 三乙胺 、 三氟乙酸酐 作用下， 以 四氢呋喃 为溶剂， 以51%的产率得到(2R,5S,7S)-1-aza-7-benzyloxycarbonylamino-8-oxo-4-thiabicyclo[3.3.0]octane-2-carbonitrile
  参考文献：
  名称：

  Constrained Peptidomimetics Reveal Detailed Geometric Requirements of Covalent Prolyl Oligopeptidase Inhibitors

  摘要：

  Prolyl oligopeptidases cleave peptides on the carboxy side of internal proline residues and their inhibition has potential in the treatment of human brain disorders. Using our docking program FITTED, we have designed a series of constrained covalent inhibitors, built from a series of bicyclic scaffolds, to study the optimal shape required for these small molecules. These structures bear nitrile functional groups that we predicted to covalently bind to the catalytic serine of the enzyme. Synthesis and biological assays using human brain-derived astrocytic cells and endothelial cells and human fibroblasts revealed that these compounds act as selective inhibitors of prolyl oligopeptidase activity compared to prolyl-dipeptidyl-aminopeptidase activity, are able to penetrate the cells and inhibit intracellular activities in intact living cells. This integrated computational and experimental study shed light oil the binding mode of inhibitors in the enzyme active site and will guide the design of future drug-like molecules.

  DOI：

  10.1021/jm901013a

文献信息

• Constrained Peptidomimetics Reveal Detailed Geometric Requirements of Covalent Prolyl Oligopeptidase Inhibitors
  作者：Janice Lawandi、Sylvestre Toumieux、Valentine Seyer、Philip Campbell、Sabine Thielges、Lucienne Juillerat-Jeanneret、Nicolas Moitessier

  DOI：10.1021/jm901013a

  日期：2009.11.12

  Prolyl oligopeptidases cleave peptides on the carboxy side of internal proline residues and their inhibition has potential in the treatment of human brain disorders. Using our docking program FITTED, we have designed a series of constrained covalent inhibitors, built from a series of bicyclic scaffolds, to study the optimal shape required for these small molecules. These structures bear nitrile functional groups that we predicted to covalently bind to the catalytic serine of the enzyme. Synthesis and biological assays using human brain-derived astrocytic cells and endothelial cells and human fibroblasts revealed that these compounds act as selective inhibitors of prolyl oligopeptidase activity compared to prolyl-dipeptidyl-aminopeptidase activity, are able to penetrate the cells and inhibit intracellular activities in intact living cells. This integrated computational and experimental study shed light oil the binding mode of inhibitors in the enzyme active site and will guide the design of future drug-like molecules.
• Metabolic Instability of Cyanothiazolidine-Based Prolyl Oligopeptidase Inhibitors: a Structural Assignment Challenge and Potential Medicinal Chemistry Implications
  作者：Paolo Schiavini、Joshua Pottel、Nicolas Moitessier、Karine Auclair

  DOI：10.1002/cmdc.201500114

  日期：2015.7

  single primary metabolite into a panel of secondary metabolites. The rapid isomerization of all seven detected molecules precluded the use of NMR spectroscopy or X‐ray crystallography for complete structural determination, presenting an interesting structure elucidation challenge. Through a combination of LC–MS analysis, synthetic work, deuterium exchange studies, and computational predictions, we were

  作为基于氰基噻唑烷的脯氨酰寡肽酶抑制剂开发的一部分，初步代谢研究表明P450酶可氧化多个位点。令人惊讶的是，深入的研究表明，在多个立体遗传学中心的差向异构是将单一主要代谢物转化为一系列次要代谢物的原因。所有七个检测到的分子的快速异构化都无法使用NMR光谱法或X射线晶体学进行完整的结构测定，从而提出了有趣的结构阐明挑战。通过结合LC-MS分析，合成工作，氘交换研究和计算预测，我们能够表征所有代谢物并阐明其在溶液中的动态行为。在药物开发的背景下，