TY - JOUR T1 - Antiplatelet Efficacy of XV459, A Novel Nonpeptide Platelet GPIIb/IIIa Antagonist: Comparative Platelet Binding Profiles with c7E3 JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 1277 LP - 1284 VL - 286 IS - 3 AU - Shaker A. Mousa AU - Jeffrey M. Bozarth AU - William Lorelli AU - Mark S. Forsythe AU - Martin J. M. C. Thoolen AU - Andrew M. Slee AU - Thomas M. Reilly AU - Paul A. Friedman Y1 - 1998/09/01 UR - http://jpet.aspetjournals.org/content/286/3/1277.abstract N2 - 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 (Kd = 0.0008 and 0.0091 μM, respectively) or unactivated human platelets (Kd = 0.0025 and 0.0092 μM, respectively). XV459 demonstrated tight association with human, baboon and (to a lesser extent) canine platelets (t½ 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. The American Society for Pharmacology and Experimental Therapeutics ER -