Human platelet alpha IIb beta 3 integrin binding affinity end specificity of SJ874: antiplatelet efficacy versus aspirin

Objective To define the affinity and specificity of SJ874, a nonpeptide ant iplatelet agent for platelet glycoprotein IIb/IIIa integrin, and to determi ne the antiplatelet efficacy of SJ874 relative to those of glycoprotein IIb /IIIa antagonists and aspirin. Methods Binding affinity and specificity of SJ874 for platelet glycoprotein Ilb/IIIa integrin were determined using integrin-mediated binding and adhe sion assays with human cells. Additionally, the antiplatelet efficacy of SJ 874 was determined and compared with those of other glycoprotein IIb/IIIa a ntagonists and aspirin using light-transmittance and laser-scattering aggre gometry. Results SJ874 inhibited aggregation of human platelets induced by 10 mu mol /l adenosine diphosphate (ADP) with a concentration for half-maximal effect of 0.046 +/- 0.005 mu mol/l using light-transmittance aggregometry. Using laser-scattering aggregometry, SJ874 was found to totally inhibit formation both of micro-aggregates and of macro-aggregates induced either by ADP or by epinephrine. In contrast, administration of 325 mg aspirin to normal hea lthy volunteers attenuated formation of macro-aggregates but not micro-aggr egates. SJ874 inhibited binding of [I-125]-fibrinogen to activated (by ADP, epinephrine, and arachidonic acid at concentrations of 100 mu mol/l each) gel-filtered human platelets with a concentration for half-maximal effect o f 0.0012 +/- 0.0005 mu mol/l. SJ874 was demonstrated to associate more tigh tly with resting human platelets than did DMP754 [1] and slightly less tigh tly than did DMP802 [2]. SJ874 was demonstrated to exhibit a high degree of specificity for platelet glycoprotein IIb/IIIa (alpha IIb/beta 3) integrin compared with other known integrins, including alpha v beta 3, alpha v bet a 5, and alpha 5 beta 1 (concentration for half-maximal effect > 100 mu mol /l). Conclusion SJ874 is a potent and specific platelet glycoprotein IIb/IIIa an tagonist with high affinity for and tight association with human platelets. These data suggest that SJ874 might have good antiplatelet utility for inh ibiting formation both of platelet micro-aggregates and of macro-aggregates of platelets and a long duration of action in humans due to its slow disso ciation from human platelets. Coron Artery Dis 11:563-570 (C) 2000 Lippinco tt Williams & Wilkins.