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Platelet Activating Factor (PAF) Antagonists

These agents may be useful in PAF-induced bronchoconstriction. In the hetrazepine class of PAF antagonist, apafant (WEB-2086) (44) has been shown to be rapidly absorbed following oral administration and produced no significant adverse effects [92]. Two other compounds—WEB-2347 (45) and E-6123 (46)—also from the hetrazepine class, have emerged as orally active derivatives with profiles superior to WEB-2086 (44).

Elastase Inhibitors

Strategies for designing inhibitors of human neutrophil elastase (HNE), the enzyme whose unrestrained action may result in the lung damage underlying the development of emphysema, has been under active research. Prolastin, the natural human aj-antitrypsin that inhibits HNE, was administered by aerosol, with demonstrated effectiveness in restoring the protease-antiprotease balance in genetic emphysema [101,102]. Several other peptide drugs when administered intratrachealy appear to have good residence times in the lung. Intratracheally administered L-6592866 (47),

a modified b-lactam HNE inhibitor, showed selective inhibition of lung HNE and blocked HNE damage to hamster lung [103]. ICI 200,880 (48) also showed a long residency time in the lung and potent HNE inhibition after intratracheal administration [104].

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