Synthesis of thrombin-inhibiting heparin mimetics without side effects

Unwanted side effects of pharmacologically active compounds can usually be eliminated by structural modifications. But the complex heterogeneous struc ture of the polysaccharide heparin(1) has limited this approach to fragment ation, leading to slightly better-tolerated heparin preparations of low mol ecular mass(2). Despite this improvement, heparin-induced thrombocytopaenia (3) (HIT), related to an interaction with platelet factor 4 (PF4) and, to a lesser extent, haemorrhages(4), remain significant side effects of heparin otherapy. Breakthroughs in oligosaccharide chemistry(5) made possible the t otal synthesis of the pentasaccharide antithrombin-binding site of heparin( 6,7). This pentasaccharide represents a new family of potential antithrombo tic drugs, devoid of thrombin inhibitory properties, and free of undesired interactions with blood and vessel components. To obtain more potent and we ll-tolerated antithrombotic drugs, we wished to synthesize heparin mimetics able to inhibit thrombin, that is, longer oligosaccharides. Like thrombin inhibition, undesired interactions are directly correlated to the charge an d the size of the molecules(8), so we had to design structures that were ab le to discriminate between thrombin and other proteins, particularly PF4. H ere we describe the use of multistep converging synthesis to obtain sulphat ed oligosaccharides that meet these requirements.