Biochemical Characterization of α-Ketooxadiazole Inhibitors of Elastases

A series of α-ketooxadiazole compounds was prepared and evaluated in vitro as potential inhibitors of human neutrophil elastase (HNE), proteinase-3 (PR-3), and porcine pancreatic elastase (PPE). Several compounds have been found to be very potent, fast, reversible, and selective inhibitors of HNE with Ki values below 100 pM. The highest kon value exceeded 107 M−1 s−1. Some α-ketooxadiazoles were also very effective against PR-3 and PPE with Ki values in the range of 5–10 nM and 0.1–2 nM, respectively. The two rings, 1,2,4- and 1,3,4-oxadiazole, are amenable to substitutions, extending the P′ side of the inhibitor and allowing additional binding interactions at S′ subsites of the enzyme. Nonpeptidic HNE inhibitors containing the oxadiazole heterocycle displayed promising oral bioavailability.