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) inhibitors of the Val-Pro-Val type has been developed. Initially, the central proline residue was replaced by nonnatural amino acids Phi ((2S,3aS,7aS)-perhydroindole-2-carboxylic acid) and Abo ((3S)-2-azabicyclo-[2.2.2]octane-3-carboxylic acid), and secondly several groups able to confer antioxidant properties to the molecule were introduced at the lipophilic N-terminal side chain. When compared to reference inhibitors, in vitro HLE inhibitory potency was maintained (10-100 nM) both with compounds containing the antioxidant moiety at the end of the N-terminal side chain and with compounds in which the N-terminal valine of the tripeptidic sequence had been replaced by a epsilon-substituted lysine. The lipidic peroxidation inhibitory potency of this series of inhibitors was found to be similar to that of the reference antioxidant compounds (around 1 microM). Moreover, HLE-induced hemorrhage in the hamster lung was effectively prevented (40-60% at 15 micrograms/kg) by most of the inhibitors tested when administered intratracheally 3 h before instillation of elastase. Among the most active analogs, compounds 11a,c,g were still active when administered 18 h before elastase. Interestingly, compound 14a was able to prevent HLE-mediated lung damage when administered 72 h prior to enzymatic challenge, indicating exceptional stability and retention in the lung. Finally, in a 14-day chronic model of emphysema in the hamster, 14a significantly conserved alveolar spaces, a marker of lung tissue destruction, and was more potent than reference inhibitor ICI 200 880. This indicates that addition of peroxidation inhibitory properties to an HLE inhibitor can provide a powerful in vivo inhibitor of pulmonary tissue destruction.
Portevin
B
B
Division D of Medicinal Chemistry, Institut de Recherche Servier, Suresnes, France.
Lonchampt
M
M
Canet
E
E
De Nanteuil
G
G
D000818:Animals; D000975:Antioxidants / Q000138:chemical synthesis / Q000494:pharmacology; D006224:Cricetinae; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D006470:Hemorrhage / Q000517:prevention & control; D006801:Humans; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors*; D015227:Lipid Peroxidation / Q000187:drug effects*; D008171:Lung Diseases / Q000139:chemically induced / Q000517:prevention & control; D008297:Male; D008647:Mesocricetus; D008862:Microsomes, Liver / Q000378:metabolism; D015394:Molecular Structure; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D013329:Structure-Activity Relationship
C106599:4-((((4-chloro-3-(((((4-hydroxy-3,5-di-tert-butylphenyl)thio)acetyl)amino)sulfonyl)phenyl)carbonyl)amino)sulfonyl)benzoyl-valyl-(perhydroindole-2-carbonyl)-valine trifluoromethyl ketone; D000975:Antioxidants; D004791:Enzyme Inhibitors; D009842:Oligopeptides; D019272:Leukocyte Elastase