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