Well over 12.5 million people in the US suffer from the occurrence and reoccurrence of myocardial infarction, stroke, PAOD and pulmonary embolism resulting in around 1 million deaths and a health care expenditure of over $US100 billion each year. Due to the morbidity associated with cardiovascular disease the development of improved therapeutic options remains a priority for both the pharmaceutical industry and clinicians (click here for a full analysis of drug development activity in this field).

First line therapy for thrombotic diseases includes the use of anticoagulants, a market worth around $US6 billion per year. Unfortunately anticoagulants in current use suffer a number of limitations including a high incidence of serious or dose limiting hemorrhage, and in the case of heparin, heparin-induced-thrombocytopenia and thrombosis syndrome. The development of anti-coagulants with a lower risk of hemorrhage is thus required. The coagulation cascade is activated via the intrinsic and extrinsic pathways. Both pathways produce factor IXa which converts factor X to factor Xa in the presence of factor VIII. The accumulation of factor Xa then converts prothrombin to thrombin, which, in turn causes the generation of clots from fibrin. The coagulant activity of thrombin involves the binding of alpha-thrombin to platelet protease-activated receptors PAR-1 and PAR-4. Johnson & Johnson researchers have recently evaluated the role of PAR-1 in thrombosis. Since primates and non-primates differ with their respect to PAR expression studies were performed using platelets from cynomolgus monkeys. Platelets were found to express primarily PAR-1 and PAR-4, thereby mirroring the profile of human platelets. The role of PAR-1 in a primate model of vascular injury-induced thrombosis was then investigated with the selective PAR-1 antagonist RWJ-58259. Time to occlusion was significantly extended after RWJ-58259 administration. Ex vivo platelet aggregation measurements indicated complete PAR-1 inhibition, as well as an operational PAR-4 response. Immunohistochemical staining of mural thrombi indicated that RWJ-58259 significantly reduced thrombus platelet deposition. Drug treatment had no effect on key hematological or coagulation parameters. These results provide direct evidence that PAR-1 is the primary receptor that mediates alpha-thrombin's prothrombotic actions in primates and suggest that PAR-1 antagonists may have potential for improved and safer treatments of thrombotic disorders in humans.

Entry date February, 2003

Adapted from Derian et al, J Pharmacol Exp Ther 2003 Feb;304(2):855-6.

Interested in collaborating with this group? Contact leaddiscovery@bioportfolio.co.uk