Elsevier

Drug Discovery Today

Volume 10, Issue 11, 1 June 2005, Pages 769-779
Drug Discovery Today

Review
Synthetic heparin derivatives as new anticoagulant drugs

https://doi.org/10.1016/S1359-6446(05)03457-4Get rights and content

The journey towards a detailed mechanistic understanding of the anticoagulant action of heparin has resulted in synthetic mimetics with improved pharmacodynamic profiles. Inspired by the ternary complex formation of heparin with antithrombin III and thrombin, the active pentasaccharide fondaparinux has been succeeded by several clinical candidates, such as SR123781, that have tailor-made factor Xa and thrombin inhibitory activities combined with less aspecific binding (e.g. binding to platelet factor 4 involved in thrombocytopenia). Novel compounds with both antithrombin III-mediated inhibition of factor Xa and direct thrombin inhibition are emerging. Org42675 is one such compound, balancing dual inhibition of factor Xa and thrombin in one anticoagulant drug, with excellent pharmacokinetic properties and strong inhibitory activity toward clot-bound thrombin.

Section snippets

Clinical aspects

Heparin has been used clinically since 1937 [1] and is a highly effective antithrombotic agent in the prevention and treatment of numerous thromboembolic disorders (http://patients.uptodate.com). Although it offers rapid anticoagulation after subcutaneous administration and is relatively inexpensive, heparin has several limitations. First, heparin is extracted from porcine intestinal mucosa or bovine intestinal or lung tissue, with the potential risk of pathogenic contamination. Since the

Synthetic pentasaccharide

When Organon and Sanofi-Synthélabo (now Sanofi-Aventis) embarked on a high-risk R&D collaboration, the pentasaccharide 2 [SR90107/Org31540 (fondaparinux); Figure 1b] was selected for further development. Compound 2 is closely related to the natural sequence of heparin, with a stabilizing methyl group at the reducing end of monosaccharide unit H [7]. Fondaparinux binds completely to ATIII, which protects the small pentasaccharide from rapid elimination [half-life (t1/2) of 17 h], enabling

Mimicking the heparin template

Heparin and the active pentasaccharide trigger binding to ATIII and inhibition of serine proteases. However, in the case of thrombin, the heparin-induced conformational change of ATIII is not sufficient to neutralize the enzyme. The unique pentasaccharide domain must be present, but heparin should also act as a negatively charged template to which both ATIII and thrombin bind simultaneously to form a ternary complex (Figure 2) [27]. The interaction between thrombin and the thrombin-binding

Designing a dual inhibitor with a mixed profile

Building on experience gained in the field of complex heparin-like pentasaccharides and direct thrombin inhibitors, the preparation of antithrombotics that can directly inhibit thrombin, as well as catalyze the ATIII-mediated inhibition of fXa, were investigated. The concept of such a dual inhibitor in which the benefits of LMWHs and direct thrombin inhibitors (Box 2) are combined is expected to elicit new pharmacological properties. Not only would such a compound be capable of inhibiting newly

Synthetic heparin derivatives

After years of intensive research, many synthetic heparin derivatives have entered the clinical arena. Structure-based approaches gave insight into the mechanism of heparin-induced activation of ATIII and provided access to novel synthetic fragments with higher potency and longer t1/2, but without notorious side effects [29, 57, 58]. R&D activities were challenged with multistep-synthesis of the most complex oligosaccharides prepared to date, both on a laboratory and production scale [29].

Note

Since 1987, Organon has been collaborating with Sanofi-Synthélabo (now Sanofi-Aventis) to develop drugs based on synthetic oligosaccharides for the treatment of atherothrombotic diseases. In January 2004, a revision of the terms of the collaboration was announced and Sanofi-Synthélabo agreed to acquire some of Organon's interests relating to Arixtra®, idraparinux and other oligosaccharides, such as the hexadecasaccharide SR123781. Organon acquired Sanofi-Synthélabo's interest relating to

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