Dual inhibition of human leukocyte elastase and lipid peroxidation: in vitro and in vivo activities of azabicyclo[2.2.2]octane and perhydroindole derivatives

Journal of Medicinal Chemistry
B PortevinG De Nanteuil

Abstract

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the end of the N-terminal side chain and with compounds in which the N-terminal valine of the tripeptidic sequence had been replaced by a epsilon-substituted lysine.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 elast...Continue Reading

References

Jan 1, 1991·Annals of the New York Academy of Sciences·J C WilliamsR D Krell
Oct 1, 1984·European Journal of Biochemistry·G D VircaH P Schnebli
Aug 1, 1995·Bioorganic & Medicinal Chemistry·G De NanteuilT J Verbeuren
Sep 1, 1955·The Journal of Clinical Investigation·R J HAVELJ H BRAGDON

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Citations

Dec 27, 2005·Bioorganic & Medicinal Chemistry·Haridas RodeHans-Hartwig Otto
Jul 17, 1998·Transplantation·Y YamaguchiM Ogawa
Feb 12, 2000·Journal of Medicinal Chemistry·D LeungD P Fairlie

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