Pyrrolidinyl pyridone and pyrazinone analogues as potent inhibitors of prolyl oligopeptidase (POP)

Bioorg Med Chem Lett. 2008 Aug 1;18(15):4360-3. doi: 10.1016/j.bmcl.2008.06.067. Epub 2008 Jun 24.

Abstract

We report the synthesis and in vitro activity of a series of novel pyrrolidinyl pyridones and pyrazinones as potent inhibitors of prolyl oligopeptidase (POP). Within this series, compound 39 was co-crystallized within the catalytic site of a human chimeric POP protein which provided a more detailed understanding of how these inhibitors interacted with the key residues within the catalytic pocket.

MeSH terms

  • Brain / drug effects
  • Brain / metabolism
  • Combinatorial Chemistry Techniques
  • Crystallography, X-Ray
  • Drug Design
  • Humans
  • Molecular Conformation
  • Molecular Structure
  • Prolyl Oligopeptidases
  • Pyridones / blood
  • Pyridones / chemical synthesis*
  • Pyridones / chemistry
  • Pyridones / pharmacology*
  • Pyrrolidines / blood
  • Pyrrolidines / chemical synthesis*
  • Pyrrolidines / chemistry
  • Pyrrolidines / pharmacology*
  • Serine Endopeptidases / drug effects*
  • Serine Proteinase Inhibitors / blood
  • Serine Proteinase Inhibitors / chemical synthesis*
  • Serine Proteinase Inhibitors / chemistry
  • Serine Proteinase Inhibitors / pharmacology*

Substances

  • Pyridones
  • Pyrrolidines
  • Serine Proteinase Inhibitors
  • Serine Endopeptidases
  • PREPL protein, human
  • Prolyl Oligopeptidases