Synthesis and evaluation of novel 8,5-fused bicyclic peptidomimetic compounds as interleukin-1β converting enzyme (ICE) inhibitors

An 8,5-fused bicyclic peptidomimetic ring system generated by a stereoselective ring metathesis reaction was elaborated into potent inhibitors of interleukin-1β converting enzyme (ICE, caspase-1). Multiple compounds were found that exhibited ICE IC50 values <10 nM and were selective over caspase-3 and caspase-8. These active analogs generally possessed good activity (IC50 values <100 nM) in a whole cell assay measuring IL-1β production. Pharmacokinetic analysis of the ethyl acetal prodrug form of a selected active lead revealed a compound with a reasonable plasma half-life (1.1 h) and good oral bioavailability (30%).

The stereoselective synthesis and biological characterization of novel 8,5-bicyclic peptidomimetic inhibitors of interleukin-1β converting enzyme are described.Figure optionsDownload as PowerPoint slide