NOVEL NONPEPTIDE ANTIPLATELET GLYCOPROTEIN IIB IIIA RECEPTOR ANTAGONIST, DMP754 - RECEPTOR-BINDING AFFINITY AND SPECIFICITY/

Objective To define the antiplatelet efficacy and specificity of the g lycoprotein llb/llla complex (GPllb/llla) antagonist prodrug DMP754 an d its free acid form, XV459. Methods and materials DMP754 has an IC50 > 1 mu mol/l, and, upon its conversion with esterases to its free acid form, demonstrated high potency (IC50 20-45 nmol/l) in inhibiting hum an platelet aggregation induced by 10 mu mol/l adenosine diphosphate, 20 mu g/ml collagen, 1 mmol/l epinephrine, 10 mu mol/l platelet activa ting factor or 0.5 IU/ml thrombin. The in-vitro rate of hydrolysis of DMP754 or XV459 is much faster with human or canine liver esterases (t (1/2) = 2.4-23 min) than with plasma esterases (t(1/2) = 5.5-7.6 h). P latelet Gpllb/llla integrin binding affinity and specificity for XV459 were determined using cell binding/adhesion assays. Results The range of IC(5)0 values of XV459 in inhibiting platelet aggregation in plate let-rich plasma obtained from 12 subjects was 0.035-0.069 mu mol/l wit h a mean IC50 of 0.050 +/- 0.003 mu mol/l. Additionally, XV459 inhibit ed platelets obtained from mongrel dogs, baboons, sheep, guinea pigs, and mice with IC(5)0 in the range 0.024-0.06 mu mol/l, and IC50 in the range 0.16-5.8 mu mol/l in pigs, rabbits, and rats, XV459 inhibited [ (125)l]-fibrinogen binding to activated human platelets with an IC50 o f 0.011 +/- 0.003 mu mol/l. XV459 demonstrated a high degree of select ivity in specifically inhibiting fibrinogen binding to the platelet in tegrin, GPllb/llla (IC50 = 0.00025 +/- 0.00005 mu mol/l) compared with inhibiting other integrins (alpha(v) beta(3), IC50 > 10 mu mol/l; or alpha(v) beta(5), alpha(5) beta(1) or alpha(4) beta(1) for which the I C50 exceeded 100 mu mol/l). Conclusion DMP754 is a potent antiplatelet agent in inhibiting platelet aggregation, and has a high specificity and affinity for human platelet GPllb/llla receptors.