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Humanneutrophil elastase (HNE) is an attractive target for treating chronicand acute inflammatory lung diseases. An optimization campaign ofthe kojic acid scaffold to develop new potent HNE inhibitors is reported. O3-Pivaloyl derivatives were shown to be themost potent inhibitors with IC5ovalues down to 80 nM.These compounds presented excellent selectivity and cytotoxicity profileswith suitable ligand efficiency. [ABSTRACT FROM AUTHOR]

Abstract: The synthesis, inhibitory activity and mode of action of oxazolidine-2,4-diones against porcine pancreatic elastase, here used as a model for human neutrophil elastase, are reported. The nature of N-substitution at the oxazolidine-2,4-dione scaffold has large effect on the inhibitory potency against elastase. N-Acyl and N-sulfonyloxazolidine-2,4-diones emerged as potent pseudo-irreversible inhibitors, displaying high second-order rate constants for PPE inactivation. The title compounds were also shown to be potent inhibitors of human neutrophil elastase (HNE) and proteinase-3, and weak inhibitors of human cathepsin G. The results herein presented show that the oxazolidine-2,4-diones represent a new promising class of serine protease inhibitors. [Copyright &y& Elsevier]