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 (IC50 values ≤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. Caspase the friendly target! The role of a nitrile electrophile as a mediator of the covalent interaction between an optimized caspase 1 inhibitor scaffold [NCGC00183434 (4)] is examined. Synthesis, SAR, hydrolytic stability, selected ADME properties and docking models are reported.