Synthesis and evaluation of tricyclic pyrrolopyrimidinones as dipeptide mimetics: inhibition of interleukin-1beta-converting enzyme

Bioorg Med Chem Lett. 2005 Oct 1;15(19):4322-6. doi: 10.1016/j.bmcl.2005.06.046.

Abstract

The application of a tricyclic pyrrolopyrimidinone scaffold for the synthesis of peptidomimetic inhibitors of interleukin-1beta-converting enzyme (ICE) is reported. The synthesis of the tricyclic scaffold and conversion of it to a variety of target ICE inhibitors were accomplished in 4-5 steps. In vitro biological evaluation of the tricyclic pyrrolopyrimidinones revealed fair to good ICE inhibitors, with the most active compound exhibiting an IC50 of 14 nM in a caspase-1 enzyme binding assay.

MeSH terms

  • Caspase Inhibitors*
  • Dipeptides / chemical synthesis*
  • Dipeptides / pharmacology
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / pharmacology
  • Heterocyclic Compounds, 3-Ring / chemical synthesis
  • Heterocyclic Compounds, 3-Ring / pharmacology
  • Humans
  • Immunologic Factors / chemical synthesis
  • Immunologic Factors / pharmacology
  • Inhibitory Concentration 50
  • Molecular Mimicry
  • Monocytes
  • Pyrimidinones / chemical synthesis*
  • Pyrimidinones / pharmacology
  • Pyrroles / chemical synthesis
  • Pyrroles / pharmacology
  • Structure-Activity Relationship

Substances

  • Caspase Inhibitors
  • Dipeptides
  • Enzyme Inhibitors
  • Heterocyclic Compounds, 3-Ring
  • Immunologic Factors
  • Pyrimidinones
  • Pyrroles