Abstract

Recent advances in the development of i.v. platelet glycoprotein αIIb/β3 integrin (GPIIb/IIIa) antagonists led to the development of either a class of small-molecular-weight antagonists with a short to ultra-short duration of antiplatelet effects (Integrelin, Tirofiban, DMP728) or a very long-acting antagonist (ReoPro). Thus the present study was undertaken to characterize the antiplatelet efficacy of a small-molecule GPIIb/IIIa antagonist, DMP754/XV459, and to determine its platelet GPIIb/IIIa receptor binding profiles. DMP754, upon its conversion with esterases to its free acid form XV459, and XV459 itself, demonstrated high potency (IC₅₀ = 0.030–0.060 μM) in inhibiting human platelet aggregation induced by ADP (100 μM), thrombin receptor agonist peptide (10 μM) or collagen (20 μg/ml) in citrate or heparin. Maximal platelet aggregation inhibition was achieved at 50 to ≥80% receptor occupancy, depending on the agonist used. Both XV459 and c7E3 bind with high affinity to either activated human platelets (K_d = 0.0008 and 0.0091 μM, respectively) or unactivated human platelets (K_d = 0.0025 and 0.0092 μM, respectively). XV459 demonstrated tight association with human, baboon and (to a lesser extent) canine platelets (t_½ of dissociation = 7 ± 0, 8 ± 1 and 1.4 ± 0.1 minutes, respectively). Both c7E3 and XV459 associate tightly with slower dissociation rates to unactivated human platelets. XV459 represents a potent antiplatelet agent in inhibiting platelet aggregation along with offering high affinity and a relatively slow dissociation rate from human platelet GPIIb/IIIa receptors that might allow for once-a-day p.o. dosage.