ReviewSynthetic heparin derivatives as new anticoagulant drugs
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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Chemical synthesis and pharmacological properties of heparin pentasaccharide analogues
2022, European Journal of Medicinal ChemistryCitation Excerpt :Total synthesis of fondaparinux has allowed to eliminate inherent limitations of animal-sourced heparin and LMWHs, and avoided the contamination in naturally occurring heparins that caused several deaths in 2008 [12]. Chemical synthesis of fondaparinux, the most successful example to date for preparing a synthetic heparin [10,13], entails more than 50 steps with an overall yield of ∼0.1% [14]; as such, fondaparinux is the most expensive drug among heparins. In particular, the total synthesis of fondaparinux is very challenging because of the difficulty in regio- and stereo-selective glycosidic bonds among the glucosamine, glucuronic acid, and iduronic acid building blocks, and the strategic installation of OSO3− and NHSO3− groups [15].
Multiple-therapy strategies via polysaccharides-based nano-systems in fighting cancer
2021, Carbohydrate PolymersCitation Excerpt :Heparin is rich in sulfate and carboxylate groups, endowing it with negatively charged property, favoring it to interact with a variety of proteins (e.g., growth factors) (Liang & Kiick, 2014). In1937 UFH was used as a blood anticoagulant in clinic because of its capability to bind with antithrombin (de Kort, Buijsman, & van Boeckel, 2005; Messmore, Wehrmacher, Coyne, & Fareed, 2004). In addition, UFH has been used for tissue regeneration in view of its ability to stabilize proteins and increase their affinity to cell receptors.
In vitro and in vivo anticoagulant activity of heparin-like biomacromolecules and the mechanism analysis for heparin-mimicking activity
2019, International Journal of Biological MacromoleculesDevelopment of low molecular weight heparin based nanoparticles for metastatic breast cancer therapy
2018, International Journal of Biological MacromoleculesA novel photocleavable heparin derivative with light controllable anticoagulant activity
2018, Carbohydrate PolymersCitation Excerpt :The anticoagulant activities of HP-DMNB conjugate and products of HP-DMNB irradiated by UV (HP-DMNB UV-4 h) were determined by APPT, PT, and TT assays, which results were shown in Fig. 5A, B and C, respectively. Structure-activity relationship (SAR) studies have shown that carboxyl groups is the essential groups for the anticoagulant activity of native HP (de Kort, Buijsman, & van Boeckel, 2005). Further, anticoagulant activity of HP depends on its concentration (Yang, Du, Huang, Wan, & Li, 2002).