N-benzoylpyrazoles are novel small-molecule inhibitors of human neutrophil elastase.

N-benzoylpyrazoles are novel small-molecule inhibitors of human neutrophil elastase. Research Abstract Details 

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N-benzoylpyrazoles are novel small-molecule inhibitors of human neutrophil elastase. Abstract Text:

Igor A Schepetkin,Andrei I Khlebnikov,Mark T Quinn,

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.

N-benzoylpyrazoles are novel small-molecule inhibitors of human neutrophil elastase. Publishing Authors By Initials

IA Schepetkin,AI Khlebnikov,MT Quinn,

For similar biochemical phenomena, metabolism, and nutrition: biochemical phenomena: structure-activity relationship research abstracts see: biochemical phenomena, metabolism, and nutrition: biochemical phenomena: structure-activity relationship research

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N-benzoylpyrazoles are novel small-molecule inhibitors of human neutrophil elastase. Journal Published:

PUBLICATION TYPE: Research Support, U.S. Gov't,

Journal: Journal of medicinal chemistry

VOLUME: 50

Page Numbers: 4928-38

Journal Abbreviation: J. Med. Chem.

ISSN: 0022-2623

DAY: 12

MONTH: 09

YEAR: 2007

N-benzoylpyrazoles are novel small-molecule inhibitors of human neutrophil elastase. Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 9716531

N-benzoylpyrazoles are novel small-molecule inhibitors of human neutrophil elastase. Keywords Mesh Terms:

KEYWORDS: Structure-Activity Relationship

MESH TERMS: chemistry

Chemical & Substance for Abstract: N-benzoylpyrazoles are novel small-molecule inhibitors of human neutrophil elastase. Information

Substance Name: Leukocyte Elastase

Registry Number: EC 3.4.21.37

Grant and Affiliation Information for N-benzoylpyrazoles are novel small-molecule inhibitors of human neutrophil elastase.

AFFILIATION: Department of Veterinary Molecular Biology, Montana State University, Bozeman, Montana 59717, USA.

Country: United States

AGENCY: United States NCRR

GRANT: RR020185

ACRONYM: RR

MEDLINETA: J Med Chem

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