Inhibition of human sputum elastase by 7-substituted 5-methyl-2-isopropylamino-4H-3,1-benzoxazin-4-ones

7-Substituted 5-methyl-2-isopropylamino-4H-3,1-benzoxazin-4-ones (BOZNs) were prepared and tested as inhibitors of human sputum elastase (HSE). The BOZNs with certain amino acid residues at the 7-position proved to be potent inhibitors of HSE. Some of the compounds also showed a high selectivity for HSE versus chymotrypsin. In a hamster model in which acute injury was induced by intratracheal administration of HSE (1.0 mg/kg), these compounds, when administered intratracheally (1.0 mg/kg) either 30 or even 240 min before challenge with HSE, significantly suppressed pulmonary hemorrhage. These findings suggest that 7-substitution of BOZN by amino acid residues can produce strong and HSE-specific inhibitors, with potential use in elastase-mediated disorders.