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.