Vol. 286, Issue 3, 1277-1284, September 1998

Antiplatelet Efficacy of XV459, A Novel Nonpeptide Platelet GPIIb/IIIa Antagonist: Comparative Platelet Binding Profiles with c7E3

Shaker A. Mousa, Jeffrey M. Bozarth, William Lorelli, Mark S. Forsythe, Martin J. M. C. Thoolen, Andrew M. Slee, Thomas M. Reilly and Paul A. Friedman

DuPont Pharmaceuticals Co., Wilmington, Delaware

Recent advances in the development of i.v. platelet glycoprotein IIb/3 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_1/2 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.