A Synthetic Antithrombin III Binding Pentasaccharide Is Now a Drug! What Comes Next?

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Abstract
Heparin is a sulfated glycosaminoglycan isolated from animal organs that has been used clinically as an antithrombotic agent since the 1940s. In the early 1980s it was discovered that a unique pentasaccharide domain in some heparin chains activates antithrombin III (AT‐III), a serine protease inhibitor that blocks thrombin and factor Xa in the coagulation cascade. Sanofi‐Synthélabo and Organon developed a synthetic analogue of this pentasaccharide. The resulting antithrombotic drug arixtra, which went on the market in the USA and Europe in 2002, shows superior antithrombotic activity and brings about AT‐III‐mediated activity against factor Xa exclusively. Structure‐based design has subsequently led to analogues with longer‐lasting activity, such as idraparinux, as well as novel conjugates and long oligosaccharides with specific anti‐Xa and antithrombin activities. The new drug candidates are more selective in their mode of action than heparin and less likely to induce thrombocytopenia.