benzyl N-[(2R,3S,7aS)-3-carbamoyl-2-methyl-5-oxo-3,6,7,7a-tetrahydro-2H-pyrrolo[2,1-b][1,3]oxazol-6-yl]carbamate | 1193377-47-7

• 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: benzyl N-[(2R,3S,7aS)-3-carbamoyl-2-methyl-5-oxo-3,6,7,7a-tetrahydro-2H-pyrrolo[2,1-b][1,3]oxazol-6-yl]carbamate
• CAS: 1193377-47-7
• 化学式: C₁₆H₁₉N₃O₅
• 分子量: 333.344
• InChiKey: LDZNZFDDBMGBOA-AYDREVNLSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.3
• 重原子数：
  24
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.44
• 拓扑面积：
  111
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  benzyl N-[(2R,3S,7aS)-3-carbamoyl-2-methyl-5-oxo-3,6,7,7a-tetrahydro-2H-pyrrolo[2,1-b][1,3]oxazol-6-yl]carbamate 在 三乙胺 、 三氟乙酸酐 作用下， 以 四氢呋喃 为溶剂， 以54%的产率得到(2S,3R,5S)-1-aza-7-benzyloxycarbonylamino-8-oxo-4-oxa-3-methylbicyclo[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
• 作为产物：
  描述：

  (2S,3R,5S)-1-aza-7-benzyloxycarbonylamino-8-oxo-4-oxa-3-methylbicyclo[3.3.0]octane-2-carboxylic acid methyl ester 在 氨 作用下， 以 甲醇 为溶剂， 反应 1.0h， 以100%的产率得到benzyl N-[(2R,3S,7aS)-3-carbamoyl-2-methyl-5-oxo-3,6,7,7a-tetrahydro-2H-pyrrolo[2,1-b][1,3]oxazol-6-yl]carbamate
  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.