Title:Discovery of Anticoagulant Drugs: A Historical Perspective
VOLUME: 9 ISSUE: 2
Author(s):Antonio Gomez-Outes, M Luisa Suarez-Gea, Gonzalo Calvo-Rojas, Ramon Lecumberri, Eduardo Rocha, Carmen Pozo-Hernandez, Ana Isabel Terleira-Fernandez and Emilio Vargas-Castrillon
Affiliation:Division of Pharmacology and Clinical Evaluation, Medicines for Human Use, Spanish Agency for Medicines and Medical Devices (AEMPS), Parque Empresarial “Las Mercedes”, Edificio 8, C/ Campezo 1, Madrid 28022, Spain.
Keywords:Anticoagulants, heparin, hirudin, history, warfarin
Abstract:The history of the traditional anticoagulants is marked by both perseverance and serendipity. The anticoagulant
effect of heparin was discovered by McLean in 1915, while he was searching for a procoagulant in dog liver. Link identified
dicumarol from spoiled sweet clover hay in 1939 as the causal agent of the sweet clover disease, a hemorrhagic disorder
in cattle. Hirudin extracts from the medicinal leech were first used for parenteral anticoagulation in the clinic in
1909, but their use was limited due to adverse effects and difficulties in achieving highly purified extracts. Heparins and
coumarins (i.e.: warfarin, phenprocoumon, acenocoumarol) have been the mainstay of anticoagulant therapy for more than
60 years. Over the past decades, the drug discovery paradigm has shifted toward rational design following a target-based
approach, in which specific proteins, or “targets”, are chosen on current understandings of pathophysiology, small
molecules that inhibit the target’s activity may be identified by high-throughput screening and, in selected cases, these
new molecules can be developed further as drugs. Despite the application of rational design, serendipity has still played a
significant role in some of the new discoveries. This review will focus on the discovery of the main anticoagulant drugs in
current clinical use, like unfractionated heparin, low-molecular-weight heparins, fondaparinux, coumarins (i.e.: warfarin,
acenocoumarol, phenprocoumon), parenteral direct thrombin inhibitors (DTIs) (i.e.: argatroban, recombinant hirudins,
bivalirudin), oral DTIs (i.e.: dabigatran) and oral direct factor Xa inhibitors (i.e.: rivaroxaban, apixaban).
