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

• Published in: Angewandte Chemie International Edition Vol. 43; no. 24; pp. 3118 - 3133
• Main Authors: Petitou, Maurice, van Boeckel, Constant A. A.
• Format: Journal Article
• Language: English
• Published: Weinheim WILEY-VCH Verlag 14-06-2004; WILEY‐VCH Verlag
• Subjects: Anticoagulants - chemistry; Anticoagulants - pharmacology; Antithrombin III - chemistry; Antithrombin III - drug effects; antithrombotics; Carbohydrate Sequence; carbohydrates; drug design; heparin; Heparin - chemistry; Heparin - pharmacology; Molecular Sequence Data; Polysaccharides - chemical synthesis; Polysaccharides - pharmacology; Serine Endopeptidases - metabolism; Structure-Activity Relationship; structure-activity relationships
• ISSN: 1433-7851; 1521-3773
• DOI: 10.1002/anie.200300640

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.
Coagulation inhibition: Heparin has been used clinically as an antithrombotic agent since the 1940s. For decades researchers have been working on the development of alternatives with improved pharmacological properties and better‐defined modes of action. The picture shows the synthetic pentasaccharide fondaparinux in the conformation it adopts when complexed with antithrombin III.