ABSTRACT
Several P4 domain derivatives of the general d-phenylglycinamide-based scaffold (2) were synthesized and evaluated for their ability to bind to the serine protease factor Xa. Some of the more potent compounds were evaluated for their anticoagulant effects in vitro. A select subset containing various P1 indole constructs was further evaluated for their pharmacokinetic properties after oral administration to rats.
Subject(s)
Antithrombin III/chemical synthesis , Antithrombin III/pharmacology , Glycine/analogs & derivatives , Anticoagulants/chemical synthesis , Anticoagulants/chemistry , Anticoagulants/pharmacology , Antithrombin III/chemistry , Crystallography, X-Ray , Factor Xa/chemistry , Factor Xa/metabolism , Glycine/chemical synthesis , Glycine/chemistry , Glycine/pharmacology , Humans , Models, Molecular , Molecular Structure , Protein Binding , Structure-Activity RelationshipABSTRACT
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.
