Oral Antiplatelet, Antithrombotic Efficacy of DMP 728, a Novel Platelet GPIIb/IIIa Antagonist

Abstract

These data suggest that DMP 728, a low-molecular-weight GPIIb/IIIa receptor antagonist, may have therapeutic potential as an oral antithrombotic agent in coronary and carotid artery thromboembolic disorders.

SCH 602539, a Protease-Activated Receptor-1 Antagonist, Inhibits Thrombosis Alone and in Combination With Cangrelor in a Folts Model of Arterial Thrombosis in Cynomolgus Monkeys

“…Although the binding of thrombin to the PAR-1 receptor represents 1 of the most potent platelet activation pathways leading to thrombosis, neither aspirin nor P2Y 12 ADP receptor antagonists (including cangrelor) significantly inhibit the PAR-1 pathway. For this reason, the addition of a PAR-1 antagonist to a P2Y 12 ADP receptor antagonist and aspirin can be expected to provide even greater antithrombotic efficacy and a further reduction in ischemic events. The presence of a synergistic effect, resulting from the combined administration of a P2Y 12 antagonist with the direct thrombin inhibitor melagatran, has been previously described.…”

“…9,[11][12][13] Cynomolgus monkeys were sedated with ketamine hydrochloride, 10 mg/kg IM, followed by anesthetization with sodium pentobarbital, 20-mg/kg IV bolus and 5-mg/kg per hour IV infusion for the duration of the experiment. The body temperature was maintained at 37°C to 39°C, and fluids infused were warmed to body temperature.…”

“…1 Although the benefits of dual antiplatelet therapy with aspirin and a P2Y 12 adenosine diphosphate (ADP) receptor antagonist have been demonstrated in a broad range of patients with atherothrombotic disease, many of these patients continue to have recurrent ischemic events. 2,3 This high residual risk can be attributed to the fact that aspirin and P2Y 12 ADP receptor antagonists (eg, clopidogrel and prasugrel) only have a partial inhibitory effect on platelet-mediated thrombosis because they each target only 1 of many platelet activation pathways. 4,5 As a result, thrombosis mediated by other platelet activation pathways, including stimulation of protease-activated receptor (PAR)-1 by thrombin, continues to occur even in the presence of aspirin and a P2Y 12 ADP receptor antagonist, leading to ischemic events.…”

“…The present study was designed to evaluate the antithrombotic efficacy of SCH 602539, a thrombin receptor antagonist selective for PAR-1 (SCH 602539 is an analog of vorapaxar [previously known as SCH 530348], a PAR-1 antagonist currently in phase 3 clinical development), alone and in combination with a P2Y 12 ADP receptor antagonist cangrelor in a Folts model of thrombosis. 11 SCH 602539 and cangrelor were chosen as the prototypes for the antagonism of the PAR-1 and P2Y 12 ADP receptors because both agents can be administered parenterally and titrated.…”

“…11 SCH 602539 and cangrelor were chosen as the prototypes for the antagonism of the PAR-1 and P2Y 12 ADP receptors because both agents can be administered parenterally and titrated.…”