Therapeutic potential of protease-activated receptor-1 antagonists

The serine protease thrombin (EC 3.4.21.5) is central to the maintenance of haemostatic balance through its coagulant, anticoagulant and platelet activating properties. In addition, this enzyme affects numerous cellular responses in a wide variety of cells, such as cell proliferation, cytokine and growth factor release, lipid metabolism and tissue remodelling. A family of G-protein-coupled protease-activated receptors (PARs) mediates these cellular actions of thrombin. While thrombin can activate three of the four PAR family members, PAR-1 represents the primary thrombin-responsive receptor in human cells. The expression of PAR-1 in platelets, the vasculature and myocardium, in cells within atherosclerotic plaque and tissues after vascular injury, indicates that this receptor plays an important role during the response to tissue injury and associated inflammatory processes. With the development of PAR-deficient mice and small-molecule antagonists, it is now clear that intervening in processes mediated by PAR-1 presents a new approach to treating a variety of disorders dependent on thrombin generation, including thrombosis and restenosis. The full potential of PAR-1 antagonists has yet to be realised, but the promise of novel therapeutics that modulate receptor function rather than thrombin's proteolytic activity, provides an alternative and, perhaps, more desirable means to dampen the pathological effects of thrombin.