A small molecule inhibitor of Caspase 1

Excerpt

A nitrile-containing propionic acid moiety as an electrophile for covalent attack by the active site cysteine residue of caspase 1 was investigated. Several cyanopropanate containing small molecules were synthesized, including one based upon the optimized peptidic scaffold of the prodrug VX-765. A number of these compounds were potent inhibitors of caspase 1 (IC₅₀s ≤ 1 nM). Examination of these small molecules versus a caspase panel demonstrated an impressive degree of selectivity for caspase 1 inhibition. The small molecular probe ML132 (CID-4462093; NCGC-00183434) is the most potent caspase 1 inhibitor reported to date. It also possesses a unique selectivity pattern relative to other reported caspase inhibitors. A number of these compounds were assessed for their hydrolytic stability and selected absorption, distribution, metabolism and elimination (ADME) properties.