d-Phenylglycinol-derived non-covalent factor Xa inhibitors: Effect of non-peptidic S4 linkage elements on affinity and anticoagulant activity

• Published in: Bioorganic & medicinal chemistry letters Vol. 17; no. 21; pp. 5801 - 5805
• Main Authors: Klimkowski, Valentine J., Watson, Brian M., Wiley, Michael R., Liebeschuetz, John, Franciskovich, Jeffry B., Marimuthu, Jothirajah, Bastian, Jolie A., Sall, Daniel J., Smallwood, Jeffrey K., Chirgadze, Nikolay Y., Smith, Gerald F., Foster, Ronald S., Craft, Trelia, Sipes, Philip, Chastain, Marcia, Sheehan, Scott M.
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 01.11.2007; Elsevier
• Subjects: Anticoagulants - chemistry; Anticoagulants - pharmacology; Biological and medical sciences; Blood. Blood coagulation. Reticuloendothelial system; Coagulation cascade; Crystallography, X-Ray; Ethanolamines; Factor Xa; Factor Xa Inhibitors; Glycine - analogs & derivatives; Glycine - chemistry; Medical sciences; Models, Molecular; Non-covalent inhibitors; Peptides - chemistry; Pharmacology. Drug treatments; Serine protease inhibitors; Serine Proteinase Inhibitors - chemistry; Serine Proteinase Inhibitors - pharmacology; Serine protease inhibitors; Factor Xa; Non-covalent inhibitors; Coagulation cascade; Nitrogen heterocycle; Coagulation Factor Xa; Non peptide compound; Anticoagulant; Modeling; Amine; Structure activity relation; Chlorine Organic compounds; Piperidine derivatives; Molecular model; Antithrombotic agent; Bicyclic compound; Aromatic compound; Chemical synthesis; Serine endopeptidases; Ether; Enzyme; Enzyme inhibitor; Inhibitor enzyme complex; Peptidases; Non covalent binding; Hydrolases; Affinity
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2007.08.051

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.