Orally active isoxazoline GPIIb/IIIa antagonists

Realization that the binding of fibrinogen to the platelet integrin α(IIb)β3 is the final common event for platelet aggregation regardless of the mechanism of activation has prompted the development of several small molecule GPIIb/IIIa antagonists for use as intravenous and/or oral antithrombotic therapies. The clinical evolution in the use of GPIIb/IIIa antagonists has achieved several significant milestones, of which the approval of c7E3-Fab by the FDA for use in patients undergoing high-risk angioplasty, and the current crop of oral agents under study in man, are particularly notable. Clearly, there is an urgent need for antiplatelet/antithrombotic drugs that are more effective than aspirin or ticlopidine for the prevention and treatment of cardiovascular and cerebrovascular thromboembolic disorders. Platelet GPIIb/IIIa receptor blockade represents a very promising therapeutic and diagnostic strategy in the treatment of thromboembolic disorders. Clinical experiences (efficacy vs. safety) gained with parenteral GPIIb/IIIa antagonists will provide valuable insights into the potential of long-term usage of oral GPIIb/IIIa antagonists which are in early clinical or late preclinical development. Various clinical trials have demonstrated the utility of glycoprotein IIb/IIIa blockade during coronary angioplasty and in patients with unstable angina. A number of large-scale trials are currently underway to widen the indications and improve efficacy and safety. Isoxazolinylacetamides, such as XR300, DMP754, and DMP802, represent a novel class of antiplatelet/antithrombotic agents with high affinity and specificity for platelet GPIIb/IIIa receptors and may have therapeutic potential as parenteral and/or oral antithrombotic agents in coronary, carotid, and peripheral arterial thromboembolic disorders.