ABSTRACT
Peptidomimetic compounds possessing a caprolactam ring constraint were prepared and evaluated as interleukin-1beta 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 IC(50) values less than 10nM in a caspase-1 enzyme assay and less than 100nM in a THP-1 whole cell assay measuring IL-1beta production. Two compounds, 13c and 13j, were found to have good oral bioavailability (>50%) in rats when administered as prodrugs.
Subject(s)
Caprolactam/chemical synthesis , Caspase Inhibitors , Enzyme Inhibitors/pharmacology , Serpins/chemical synthesis , Viral Proteins/chemical synthesis , Animals , Biological Availability , Caprolactam/chemistry , Caprolactam/pharmacology , Crystallography, X-Ray , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Hydrogen Bonding , Interleukin-1beta/metabolism , Male , Models, Molecular , Molecular Conformation , Molecular Structure , Rats , Rats, Sprague-Dawley , Serpins/pharmacology , Structure-Activity Relationship , Viral Proteins/pharmacologyABSTRACT
An 8,5-fused bicyclic peptidomimetic ring system generated by a stereoselective ring metathesis reaction was elaborated into potent inhibitors of interleukin-1beta 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-1beta 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%).
