5-Methyl-4H-3,1-benzoxazin-4-one derivatives: specific inhibitors of human leukocyte elastase.

Inhibitors of human leukocyte elastase (HLE) may exert potent therapeutic effects on pulmonary emphysema, adult respiratory distress syndrome and other diseases involving tissue degradation. 7-(4-Chlorophenylsulfonyl-L-glutanyl)amino-5-methyl-2-isopro pylamino-4H-3,1- benzoxazin-4-one (TEI-5624) and 7-(4-chlorophenylsulfonyl-L-lysyl)amino-5-methyl-2- isopropylamino-4H-3,1-benzoxazin-4-one (TEI-6344), two derivatives of 5-methyl-4H-3,1-benzoxazin-4-one, showed strong and highly specific inhibition of human sputum elastase (HSE), which is equivalent to HLE, with Ki values of 6.91 and 16.3 nM, respectively. The selectivity of TEI-5624 for HSE vs. several proteinases ranged from 300-fold to 45,000-fold in favor of HSE. TEI-5624 and TEI-6344 also efficiently prevented degradation of insoluble elastin by stimulated polymorphonuclear leukocytes. The elastase inhibitory capacity of these compounds was not affected by treatment with stimulated polymorphonuclear leukocytes or Pseudomonas aeruginosa-origin elastase. When administered intratracheally to hamsters. TEI-5624 and TEI-6344 were eliminated from the lung with half-times of 85 and 240 min, respectively. In acute injury induced by intratracheal administration of HSE in hamsters, these compounds significantly suppressed pulmonary hemorrhage when administered intratracheally (1 mg/kg) either 30 or 240 min before challenge with HSE (1 mg/kg). HSE-induced emphysema in hamsters was also prevented by TEI-5624 (1 mg/kg) administered intratracheally 7 hr after HSE administration (1 mg/kg). These results suggest that TEI-5624 and TEI-6344 may be useful therapeutic agents for the treatment of HLE-mediated diseases.