A synthetic antithrombin III binding pentasaccharide is now a drug! What comes next?
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.
Petitou
Maurice
M
Département Cardiovasculaire/Thrombose, Sanofi-Synthélabo, 195 route d'Espagne, 31036 Toulouse cedex, France. maurice.petitou@sanofi-synthélabo.com
van Boeckel
Constant A A
CA
D000925:Anticoagulants / Q000737:chemistry* / Q000494:pharmacology*; D000990:Antithrombin III / Q000737:chemistry* / Q000187:drug effects; D002240:Carbohydrate Sequence; D000077425:Fondaparinux; D006493:Heparin / Q000737:chemistry* / Q000494:pharmacology*; D008969:Molecular Sequence Data; D011134:Polysaccharides / Q000138:chemical synthesis* / Q000494:pharmacology*; D012697:Serine Endopeptidases / Q000378:metabolism; D013329:Structure-Activity Relationship
D000925:Anticoagulants; D011134:Polysaccharides; D000990:Antithrombin III; D006493:Heparin; D012697:Serine Endopeptidases; D000077425:Fondaparinux