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  • Review Article
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A new oral anticoagulant: the 50-year challenge

Nature Reviews Drug Discovery volume 3, pages 649–659 (2004)Cite this article

Key Points

  • During the twentieth century, it was gradually recognized that thrombosis is a major cause of morbidity and mortality in the Western world. There is therefore a great need for effective prophylaxis and treatment of thromobsis, and the use of oral anticoagulants is extensive.

  • However, traditional oral anticoagulants have several drawbacks. Warfarin, the most commonly used oral anticoagulant, has a narrow therapeutic window, and suffers from frequent drug–drug and food–drug interactions, and so requires careful monitoring of its anticoagulant effects.

  • So, there is a strong medical need for a well-tolerated, novel oral anticoagulant with a wide therapeutic window, plus the combination of favourable absorption, distribution and metabolism and elimination properties to enable predictable protection without coagulation monitoring.

  • In response to this need, our team embarked on a project in the mid-1980s with the aim of devising an improved oral anticoagulant. Thrombin, a protease that has a key role in blood coagulation, was chosen as the target.

  • This article concentrates on the preclinical development of the first oral direct thrombin inhibitor ximelagatran (Exanta; AstraZeneca).

Abstract

It is rare for any drug introduced more than 50 years ago to remain unsurpassed today; yet the oral prevention and treatment of thrombosis are still achieved by the use of the vitamin K antagonists (coumarins), such as warfarin, which were introduced in the 1940s and 1950s. For these anticoagulants, careful monitoring of the effect is needed to avoid bleeding or loss of efficacy. On the basis of the need for improved oral anticoagulants, a goal was set in 1985 to develop a new oral anticoagulant that could replace the vitamin K antagonists. After providing some medical and historical context, this article discusses the challenges facing the multidisciplinary team of scientists who were involved in the project leading to the discovery of the anticoagulant ximelagatran (Exanta; AstraZeneca), the first oral direct thrombin inhibitor.

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Figure 1: Blood coagulation.
Figure 2: The target and the chemical starting point.
Figure 3: A schematic representation of the development of chemistry of ximelagatran.
Figure 4: Binding of melagatran and fibrinopeptide A to thrombin.
Figure 5: Antithrombotic effects and bleeding in the rat.
Figure 6: A comparison of properties of melagatran and ximelagatran.
Figure 7: Pharmacokinetic profile of ximelagatran.

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Acknowledgements

The discoveries of ximelagatran and melagatran and their development and documentation for clinical use are the result of hard work in dedicated, multidisciplinary teams within AstraZeneca. Also important have been the skillful advice and participation of many physicians in the large clinical study programme. Consequently, many share the honour of this long-term project that led to Exanta.

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  1. AstraZeneca R&D Mölndal, Mölndal, S-431 83, Sweden

    David Gustafsson, Ruth Bylund, Thomas Antonsson, Ingemar Nilsson, Jan-Erik Nyström, Ulf Eriksson, Ulf Bredberg & Ann-Catrine Teger-Nilsson

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Correspondence to David Gustafsson.

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Competing interests

D. G., R. B., T. A., I. N., J.-E. N., U. E. and U. B. are all employees of AstraZeneca. A.-C. T.-N. was an employee of AstraZeneca but retired some years ago.

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DATABASES

Entrez Gene

Fibrinogen

FXa

thrombin

FURTHER INFORMATION

Encyclopedia of Life Sciences

Blood coagulation

venous thrombosis

Glossary

THROMBUS

An aggregation of platelets and fibrin with entrapped cells, mainly erythrocytes, in a blood vessel or a cardiac cavity. In a vessel, the thrombus frequently causes occlusion, thereby hindering blood flow.

MYOCARDIAL INFARCTION

Commonly known as a heart attack, this is death of part of the heart muscle due to sudden loss of blood supply. Typically, the loss of supply is caused by complete blockage of a coronary artery by a blood clot.

RULE OF FIVE

Identifies several key properties that should be considered for compounds with oral delivery in mind. These properties are molecular mass <500 Da, cLogP <5, number of hydrogen-bond donors <5 and number of hydrogen-bond acceptors <10.

ACTIVATED PARTIAL THROMBOPLASTIN TIME

Plasma coagulation assay, originally developed for monitoring the effects of unfractionated heparin, in which plasma coagulation is activated in two steps.

pKa

The pKa for any group is the pH at which it would be protonated in 50% of molecules. More molecules will become protonated with decreasing pH, and vice versa.

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Gustafsson, D., Bylund, R., Antonsson, T. et al. A new oral anticoagulant: the 50-year challenge. Nat Rev Drug Discov 3, 649–659 (2004). https://doi.org/10.1038/nrd1466

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