Synthesis and evaluation of unsaturated caprolactams as interleukin-1β converting enzyme (ICE) inhibitors

Peptidomimetic compounds possessing a caprolactam ring constraint were prepared and evaluated as interleukin-1β converting enzyme (ICE) inhibitors. The caprolactam ring was used to constrain the P3 region of our inhibitors. This strategy proved to be effective for the synthesis of ICE inhibitors, maintaining key hydrogen bond interactions with the enzyme and invoking a preferred conformation for binding. Several compounds exhibited IC50 values less than 10 nM in a caspase-1 enzyme assay and less than 100 nM in a THP-1 whole cell assay measuring IL-1β production. Two compounds, 13c and 13j, were found to have good oral bioavailability (>50%) in rats when administered as prodrugs.

Peptidomimetic compounds possessing a caprolactam ring constraint were prepared as interleukin-1β converting enzyme (ICE) inhibitors. Several compounds exhibited significant potency in vitro (<10 nM) and excellent bioavailability (F > 50%) in rats.Figure optionsDownload as PowerPoint slide