d-Phenylglycinol-derived non-covalent factor Xa inhibitors: Effect of non-peptidic S4 linkage elements on affinity and anticoagulant activity
Autor: | Scott Martin Sheehan, Nikolay Y. Chirgadze, Gerald F. Smith, Jolie Anne Bastian, Michael Robert Wiley, Trelia J. Craft, Daniel Jon Sall, Jeffrey K. Smallwood, Jothirajah Marimuthu, John Walter Nr Macclesfield Liebeschuetz, Marcia K. Chastain, Philip Sipes, Jeffry Bernard Franciskovich, Brian Morgan Watson, Ronald S. Foster, Valentine J. Klimkowski |
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Rok vydání: | 2007 |
Předmět: |
Models
Molecular Serine Proteinase Inhibitors Molecular model medicine.drug_mechanism_of_action Stereochemistry Clinical Biochemistry Factor Xa Inhibitor Glycine Pharmaceutical Science Peptide Ether Crystallography X-Ray Biochemistry chemistry.chemical_compound Amide Drug Discovery medicine Molecular Biology chemistry.chemical_classification Bicyclic molecule biology Organic Chemistry Anticoagulants chemistry Ethanolamines Enzyme inhibitor biology.protein Molecular Medicine Peptides Factor Xa Inhibitors |
Zdroj: | Bioorganic & Medicinal Chemistry Letters. 17:5801-5805 |
ISSN: | 0960-894X |
Popis: | Analogs to a series of D-phenylglycinamide-derived factor Xa inhibitors were discovered. It was found that the S4 amide linkage can be replaced with an ether linkage to reduce the peptide character of the molecules and that this substitution leads to an increase in binding affinity that is not predicted based on modeling. Inhibitors which incorporate ether, amino, or alkyl S4 linkage motifs exhibit similar levels of binding affinity and also demonstrate potent in vitro functional activity, however, binding affinity in this series is strongly dependent on the nature of the S1 binding element. |
Databáze: | OpenAIRE |
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