SYNTHESIS AND PHARMACOLOGICAL PROPERTIES OF A CLOSE ANALOG OF AN ANTITHROMBOTIC PENTASACCHARIDE (SR-90107A ORG-31540)

The synthetic pentasaccharide (1) corresponding to the heparin sequenc e 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 b eing replaced by sulfate esters and hydroxyl groups being methylated. These structural modifications allow a simpler and more efficient synt hesis of such anionic oligosaccharides. Affinity for human AT III, ant i-factor Xa activity, ability to inhibit thrombin generation, antithro mbotic activity in a rat model of venous thrombosis, and elimination h alf-life in the rat have been determined for 1 and 34. Surprisingly, i ntroduction of O-sulfates in place of N-sulfates, and methylation of h ydroxyl groups, contributes to reinforce the binding to AT III, result ing in an improved pharmacological profile.