Add time:08/28/2019         Source:sciencedirect.com

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%).

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