Biochemical characterization of alpha-ketooxadiazoie inhibitors of elastases

A series of alpha-ketooxadiazole compounds was prepared and evaluated in vi tro as potential inhibitors of human neutrophil elastase (HNE), proteinase- 3 (PR-3), and porcine pancreatic elastase (PPE). Several compounds have bee n found to be very potent, fast, reversible, and selective inhibitors of HN E with K-i values below 100 pM. The highest k(on) value exceeded 10(7) M-1 s(-1). Some alpha-ketooxadiazoles were also very effective against PR-3 and PPE with K-i values in the range of 5-10 nM and 0.1-2 nM, respectively. Th e two rings, 1,2,4- and 1,3,4-oxadiazole, are amenable to substitutions, ex tending the P' side of the inhibitor and allowing additional binding intera ctions at S' subsites of the enzyme. Nonpeptidic HNE inhibitors containing the oxadiazole heterocycle displayed promising oral bioavailability. (C) 19 99 Academic Press.