Antiplatelet Efficacy and Specificity of DMP728, a Novel Platelet GPIIb/llla Receptor Antagonist

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Abstract
The present study was undertaken to define the platelet GPIIb/IIIa affinity and specificity of DMP728, the cyclic [(D-2-aminobutyrate-N-methyl-L-arginyl-glycyl-L-aspartyl)-3-aminomethyl-benzoic acid] methane sulfonate. DMP728 demonstrated similar potency (IC50 = 0.046 ± 0.002 µM) in inhibiting human platelet aggregation induced by various agonists or combination of agonists as assessed either by light transmittance aggregometry or impedance techniques. Similarly, DMP728 inhibited (IC50 = 2.3 ± 0.8 nM) with equipotency in inhibiting 125I-fibrinogen binding to human gel-purified platelets regardless of the agonist used. In purified human GPIIb/IIIa ELISA, DMP728 demonstrated a competitive high affinity binding (Ki = 0.4 nM). Additionally, a high binding affinity (Kd = 0.1 nM) of 3H-DMP728 was demonstrated in human platelets. Furthermore, a platelet deaggregatory efficacy was shown. DMP728 demonstrated a high degree of specificity for platelet GPIIb/IIIa (α2/β3) as compared to other integrins on endothelial cells (vitronectin receptors), platelets GPIb/1X, αv/β3, and other integrins on leukocytes or nonintegrin-related systems. In conclusion, DMP728 is a novel anti-platelet agent with high affinity and specificity for platelet GPIIb/IIIa.

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