Human Neutrophil Elastase Phosphonic Inhibitors with Improved Potency of Action
| Autor: | Łukasz Winiarski, Józef Oleksyszyn, Marcin Sieńczyk |
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| Rok vydání: | 2012 |
| Předmět: |
Models
Molecular Proteases Stereochemistry Organophosphonates Peptide Serine Catalytic Domain Drug Discovery medicine Humans Protease Inhibitors Pancreatic elastase chemistry.chemical_classification Chymotrypsin biology Elastase Diastereomer Trypsin Solubility Biochemistry chemistry Drug Design biology.protein Molecular Medicine Leukocyte Elastase Peptides medicine.drug |
| Zdroj: | Journal of Medicinal Chemistry. 55:6541-6553 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm300599x |
| Popis: | Herein, we present the synthesis and the measurement of the inhibitory activity of novel peptidyl derivatives of α-aminoalkylphosphonate diaryl esters as human neutrophil elastase inhibitors. Their selectivity against other serine proteases, including porcine pancreatic elastase, chymotrypsin, and trypsin, was also demonstrated. We also describe the preparation of single peptide diastereomers. The most active and selective compound developed possessed a k(inact)/K(I) of 2353000 M(-1) s(-1), which is the most potent irreversible peptidyl inhibitor of human neutrophil elastase reported to date. The peptidyl inhibitors were demonstrated to be stable in PBS buffer and human plasma, as were their complexes with HNE. |
| Databáze: | OpenAIRE |
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