title: Discovery of anticoagulant drugs: a historical perspective.
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).
authors.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. agomezo@aemps.es
authors.forename: Antonio
authors.initials: A
authors.lastname: Gómez-Outes
authors.forename: Ma Luisa
authors.initials: ML
authors.lastname: Suárez-Gea
authors.forename: Gonzalo
authors.initials: G
authors.lastname: Calvo-Rojas
authors.forename: Ramón
authors.initials: R
authors.lastname: Lecumberri
authors.forename: Eduardo
authors.initials: E
authors.lastname: Rocha
authors.forename: Carmen
authors.initials: C
authors.lastname: Pozo-Hernández
authors.forename: Ana Isabel
authors.initials: AI
authors.lastname: Terleira-Fernández
authors.forename: Emilio
authors.initials: E
authors.lastname: Vargas-Castrillón
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000266:history* / Q000494:pharmacology / Q000627:therapeutic use; D001778:Blood Coagulation Disorders / Q000188:drug therapy / Q000266:history; D003374:Coumarins / Q000266:history* / Q000627:therapeutic use; D055808:Drug Discovery / Q000266:history; D065427:Factor Xa Inhibitors; D006493:Heparin / Q000266:history* / Q000494:pharmacology / Q000627:therapeutic use; D049673:History, 20th Century; D006801:Humans; D009844:Oligosaccharides / Q000266:history* / Q000627:therapeutic use; D013927:Thrombosis / Q000188:drug therapy / Q000266:history
chemical_list: D000925:Anticoagulants; D003374:Coumarins; D065427:Factor Xa Inhibitors; D009844:Oligosaccharides; D006493:Heparin