A series of 4-(acyloxy)- and 4,4'-bis(acyloxy)benzophenones were synthesized. Some of them, pivalates (trimethylacetates) and isobutyrates in particular, were found to be potent and selective inhibitors of human neutrophil (leukocyte) elastase. A series of 2-[(acyloxy)methyl]-5-(acyloxy)-4-pyrones were synthesized regioselectively from kojic acid. The 4-pyrones bearing a long chain acyl group at the 2-position and either pivaloyloxy or isobutyryloxy at the 5-position were potent and selective inhibitors of the human elastase. A number of analogues and derivatives in both series were synthesized in order to study the structure-activity relationship as summarized in Tables I-VI and in Tables IX and X. The inhibition was selective to human neutrophil elastase. No inhibition of porcine pancreatic elastase or bovine pancreatic chymotrypsin (Tables VII and XI) was observed. The most likely mechanism of inhibition is discussed. The implication of these findings for the treatment of rheumatoid arthritis and emphysema is outlined.