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Human platelet αIIbβ3 integrin binding affinity and specificity of SJ874: antiplatelet efficacy versus aspirin

Mousa, Shaker A. ; Forsythe, Mark ; Bozarth, Jeffrey ; Jin, Fuqiang ; Confalone, Pat N.

Therapy and Prevention
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Objective To define the affinity and specificity of SJ874, a nonpeptide antiplatelet agent for platelet glycoprotein IIb/IIIa integrin, and to determine 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 IIb/IIIa integrin were determined using integrin-mediated binding and adhesion assays with human cells. Additionally, the antiplatelet efficacy of SJ874 was determined and compared with those of other glycoprotein IIb/IIIa antagonists and aspirin using light-transmittance and laser-scattering aggregometry.

Results SJ874 inhibited aggregation of human platelets induced by 10 μmol/l adenosine diphosphate (ADP) with a concentration for half-maximal effect of 0.046 ± 0.005 μmol/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 healthy volunteers attenuated formation of macro-aggregates but not micro-aggregates. SJ874 inhibited binding of [ 125 I]-fibrinogen to activated (by ADP, epinephrine, and arachidonic acid at concentrations of 100 μmol/l each) gel-filtered human platelets with a concentration for half-maximal effect of 0.0012 ± 0.0005 μmol/l. SJ874 was demonstrated to associate more tightly with resting human platelets than did DMP754 [1] and slightly less tightly than did DMP802 [2]. SJ874 was demonstrated to exhibit a high degree of specificity for platelet glycoprotein IIb/IIIa (αIIb/β3) integrin compared with other known integrins, including αvβ3, αvβ5, and α5β1 (concentration for half-maximal effect > 100 μmol/l).

Conclusion SJ874 is a potent and specific platelet glycoprotein IIb/IIIa antagonist with high affinity for and tight association with human platelets. These data suggest that SJ874 might have good antiplatelet utility for inhibiting formation both of platelet micro-aggregates and of macro-aggregates of platelets and a long duration of action in humans due to its slow dissociation from human platelets.

DuPont Pharmaceuticals Co., Wilmington, Delaware, USA.

Correspondence and requests for reprints to Shaker A. Mousa, PhD, MBA, FACC, DuPont Pharmaceuticals Company, Experimental Station, E400/3470, 141 and Henry Clay Road, Wilmington, DE 19880-0400, USA. Tel: +1 302 695 8418; fax: +1 302 695 7407; e-mail: shaker.a.mousa@dupontpharma.com

Received 22 December 1999

Revised 10 March 2000

Accepted 17 March 2000

© 2000 Lippincott Williams & Wilkins, Inc.