5-METHYL-4H-3, 1-BENZOXAZIN-4-ONE DERIVATIVES - SPECIFIC INHIBITORS OF HUMAN-LEUKOCYTE ELASTASE

Inhibitors of human leukocyte elastase (HLE) may exert potent therapeu tic effects on pulmonary emphysema, adult respiratory distress syndrom e and other diseases involving tissue degradation. 5-methyl-2-iso-prop ylamino-4H-3,1-benzoxazin-4-one (TEI-5624) and 7-(4-chlo -5-methyl-2-i sopropylamino-4H-3,1-benzoxazin-4-one (TEI-6344), two derivatives of 5 -methyl-4H-3,1-benzoxazin-4-one, showed strong and highly specific inh ibition of human sputum elastase (HSE), which is equivalent to HLE, wi th K(i) values of 6.91 and 16.3 nM, respectively. The selectivity of T EI-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 prevente d degradation of insoluble elastin by stimulated polymorphonuclear leu kocytes. The elastase inhibitory capacity of these compounds was not a ffected by treatment with stimulated polymorphonuclear leukocytes or P seudomonas aeruginosa-origin elastase. When administered intratracheal ly to hamsters, TEI-5624 and TEI-6344 were eliminated from the lung wi th half-times of 85 and 240 min, respectively. In acute injury induced by intratracheal administration of HSE in hamsters, these compounds s ignificantly suppressed pulmonary hemorrhage when administered intratr acheally (1 mg/kg) either 30 or 240 min before challenge with HSE (1 m g/kg). HSE-induced emphysema in hamsters was also prevented by TEI-562 4 (1 mg/kg) administered intratracheally 7 hr after HSE administration (1 mg/kg). These results suggest that TEI-5624 and TEI-6344 may be us eful therapeutic agents for the treatment of HLE-mediated diseases.