A highly potent and selective caspase 1 inhibitor that utilizes a key 3-cyanopropanoic acid moiety

Herein, we examine the potential of a nitrile-containing propionic acid moiety as an electrophile for covalent attack by the active-site cysteine residue of Caspase 1. The syntheses of several cyanopropanate-containing small molecules based on the optimized peptidic scaffold of prodrug VX-765 were accomplished. These compounds were found to be potent inhibitors of Caspase 1 (IC(50) values < or =1 nM). Examination of these novel small molecules against a Caspase panel demonstrated an impressive degree of selectivity for Caspase 1 inhibition over other Caspase isozymes. Assessment of hydrolytic stability and selected ADME properties highlighted these agents as potentially useful tools for studying Caspase 1 down-regulation in various settings, including in vivo analyses.