N-Benzoylpyrazoles Are Novel Small-Molecule Inhibitors of Human Neutrophil Elastase
Identifieur interne : 003811 ( Main/Exploration ); précédent : 003810; suivant : 003812N-Benzoylpyrazoles Are Novel Small-Molecule Inhibitors of Human Neutrophil Elastase
Auteurs : Igor A. Schepetkin [Russie] ; Andrei I. Khlebnikov [Russie] ; Mark T. Quinn [Russie, États-Unis]Source :
- Journal of Medicinal Chemistry [ 0022-2623 ] ; 2007.
Abstract
Human neutrophil elastase (NE) plays an important role in the pathogenesis of pulmonary disease. Using high-throughput chemolibrary screening, we identified 10 N-benzoylpyrazole derivatives that were potent NE inhibitors. Nine additional NE inhibitors were identified through further screening of N-benzoylpyrazole analogues. Evaluation of inhibitory activity against a range of proteases showed high specificity for NE, although several derivatives were also potent inhibitors of chymotrypsin. Analysis of reaction kinetics and inhibitor stability revealed that N-benzoylpyrazoles were pseudoirreversible competitive inhibitors of NE. Structure−activity relationship (SAR) analysis demonstrated that modification of N-benzoylpyrazole ring substituents modulated enzyme selectivity and potency. Furthermore, molecular modeling of the binding of selected active and inactive compounds to the NE active site revealed that active compounds fit well into the catalytic site, whereas inactive derivatives contained substituents or conformations that hindered binding or accessibility to the catalytic residues. Thus, N-benzoylpyrazole derivatives represent novel structural templates that can be utilized for further development of efficacious NE inhibitors.
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DOI: 10.1021/jm070600+
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Schepetkin</name><affiliation wicri:level="1"><country xml:lang="fr">Russie</country><wicri:regionArea>Department of Veterinary Molecular Biology, Montana State University, Bozeman, Montana 59717, and Department of Chemistry,Altai State Technical University, Barnaul 656038</wicri:regionArea><wicri:noRegion>Barnaul 656038</wicri:noRegion></affiliation><affiliation></affiliation></author><author><name sortKey="Khlebnikov, Andrei I" sort="Khlebnikov, Andrei I" uniqKey="Khlebnikov A" first="Andrei I." last="Khlebnikov">Andrei I. Khlebnikov</name><affiliation wicri:level="1"><country xml:lang="fr">Russie</country><wicri:regionArea>Department of Veterinary Molecular Biology, Montana State University, Bozeman, Montana 59717, and Department of Chemistry,Altai State Technical University, Barnaul 656038</wicri:regionArea><wicri:noRegion>Barnaul 656038</wicri:noRegion></affiliation><affiliation></affiliation></author><author><name sortKey="Quinn, Mark T" sort="Quinn, Mark T" uniqKey="Quinn M" first="Mark T." last="Quinn">Mark T. Quinn</name><affiliation wicri:level="1"><country xml:lang="fr">Russie</country><wicri:regionArea>Department of Veterinary Molecular Biology, Montana State University, Bozeman, Montana 59717, and Department of Chemistry,Altai State Technical University, Barnaul 656038</wicri:regionArea><wicri:noRegion>Barnaul 656038</wicri:noRegion></affiliation><affiliation></affiliation><affiliation wicri:level="1"><country wicri:rule="url">États-Unis</country></affiliation></author></analytic><monogr></monogr><series><title level="j" type="main">Journal of Medicinal Chemistry</title><title level="j" type="abbrev">J. Med. Chem.</title><idno type="ISSN">0022-2623</idno><idno type="eISSN">1520-4804</idno><imprint><publisher>American Chemical Society</publisher><date type="e-published">2007</date><date type="published">2007</date><biblScope unit="vol">50</biblScope><biblScope unit="issue">20</biblScope><biblScope unit="page" from="4928">4928</biblScope><biblScope unit="page" to="4938">4938</biblScope></imprint><idno type="ISSN">0022-2623</idno></series></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0022-2623</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract">Human neutrophil elastase (NE) plays an important role in the pathogenesis of pulmonary disease. Using high-throughput chemolibrary screening, we identified 10 N-benzoylpyrazole derivatives that were potent NE inhibitors. Nine additional NE inhibitors were identified through further screening of N-benzoylpyrazole analogues. Evaluation of inhibitory activity against a range of proteases showed high specificity for NE, although several derivatives were also potent inhibitors of chymotrypsin. Analysis of reaction kinetics and inhibitor stability revealed that N-benzoylpyrazoles were pseudoirreversible competitive inhibitors of NE. Structure−activity relationship (SAR) analysis demonstrated that modification of N-benzoylpyrazole ring substituents modulated enzyme selectivity and potency. Furthermore, molecular modeling of the binding of selected active and inactive compounds to the NE active site revealed that active compounds fit well into the catalytic site, whereas inactive derivatives contained substituents or conformations that hindered binding or accessibility to the catalytic residues. Thus, N-benzoylpyrazole derivatives represent novel structural templates that can be utilized for further development of efficacious NE inhibitors.</div></front></TEI><affiliations><list><country><li>Russie</li><li>États-Unis</li></country></list><tree><country name="Russie"><noRegion><name sortKey="Schepetkin, Igor A" sort="Schepetkin, Igor A" uniqKey="Schepetkin I" first="Igor A." last="Schepetkin">Igor A. Schepetkin</name></noRegion><name sortKey="Khlebnikov, Andrei I" sort="Khlebnikov, Andrei I" uniqKey="Khlebnikov A" first="Andrei I." last="Khlebnikov">Andrei I. Khlebnikov</name><name sortKey="Quinn, Mark T" sort="Quinn, Mark T" uniqKey="Quinn M" first="Mark T." last="Quinn">Mark T. Quinn</name></country><country name="États-Unis"><noRegion><name sortKey="Quinn, Mark T" sort="Quinn, Mark T" uniqKey="Quinn M" first="Mark T." last="Quinn">Mark T. Quinn</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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