Journal of Medicinal Chemistry · 1997 · 59 citations · 12 references
MedicineBiochemistryPharmacologyGlycobiologyHemostasisStructure-activity RelationshipsAnticoagulant TherapyAntithrombotic TherapyN-linked GlycosylationNatural Anticoagulant SystemsO-linked GlycosylationThrombosis PreventionAnticoagulant Effects On Thrombin GenerationAntithrombin FunctionHeparin-protein InteractionsOligosaccharide BindingOligosaccharide CharacterizationOligosaccharide Natural ProductsOligosaccharide SynthesisPharmacological Profiling
The synthetic pentasaccharide (1) corresponding to the heparin sequence which binds to, and activates, antithrombin III (AT III) is a potent antithrombotic compound in several animal models of venous thrombosis. We describe here the preparation and the pharmacological properties of 34, an analogue of oligosaccharide 1 with the latter's N-sulfates being replaced by sulfate esters and hydroxyl groups being methylated. These structural modifications allow a simpler and more efficient synthesis of such anionic oligosaccharides. Affinity for human AT III, anti-factor Xa activity, ability to inhibit thrombin generation, antithrombotic activity in a rat model of venous thrombosis, and elimination half-life in the rat have been determined for 1 and 34. Surprisingly, introduction of O-sulfates in place of N-sulfates, and methylation of hydroxyl groups, contributes to reinforce the binding to AT III, resulting in an improved pharmacological profile.
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J Choay, Maurice Petitou, J C Lormeau et al. · Biochemical and Biophysical Research Communications · 1983 · 652 citations