DUAL INHIBITION OF HUMAN-LEUKOCYTE ELASTASE AND LIPID-PEROXIDATION - IN-VITRO AND IN-VIVO ACTIVITIES OF AZABICYCLO[2.2.2]OCTANE AND PERHYDROINDOLE DERIVATIVES

A series of potent and selective human leukocyte elastase (HLE) inhibi tors of the Val-Pro-Val type has been developed. Initially, the centra l proline residue was replaced by nonnatural amino acids Phi ((2S,3aS, 7aS)-perhydroindole-2-carboxy acid) and Abo ((3S)-2-azabicyclo[2.2.2]o ctane-3-carboxylic acid), and secondly several groups able to confer a ntioxidant properties to the molecule were introduced at the lipophili c N-terminal side chain. When compared to reference inhibitors, in vit ro HLE inhibitory potency was maintained (10-100 nM) both with compoun ds containing the antioxidant moiety at the end of the N-terminal side chain and with compounds in which the N-terminal valine of the tripep tidic sequence had been replaced by a epsilon-substituted lysine. The lipidic peroxidation inhibitory potency of this series of inhibitors w as found to be similar to that of the reference antioxidant compounds (around 1 mu M). Moreover, HLE-induced hemorrhage in the hamster lung was effectively prevented (40-60% at 15 mu g/ kg) by most of the inhib itors tested when administered intratracheally 3 h before instillation of elastase. Among the most active analogs, compounds 11a,c,g were st ill active when administered 18 h before elastase. Interestingly, comp ound 14a was able to prevent HLE-mediated lung damage when administere d 72 h prior to enzymatic challenge, indicating exceptional stability and retention in the lung. Finally, in a 14-day chronic model of emphy sema in the hamster, 14a significantly conserved alveolar spaces, a ma rker of lung tissue destruction, send was more potent; than reference inhibitor ICI 200 880. This indicates that addition of peroxidation in hibitory properties to an HLE inhibitor can provide a powerful in vivo inhibitor of pulmonary tissue destruction.