A Highly Potent and Selective Caspase 1 Inhibitor that Utilizes a Key 3-Cyanopropanoic Acid Moiety
Graphical Abstract
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.
Abstract
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.
