Comparative Antiplatelet Effects of the Active Metabolites of CS-747 (Prasugrel, LY640315) and Clopidogrel

Abstract number: P2299

Jakubowski¹ JA, Sugidachi² A, Ogawa² T, Isobe² T, Shimoji² T, Suzuki² N, Asai² F

¹¹Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, USA ²²Pharmacology and Molecular Biology Research Laboratories, Sankyo Co. Ltd., Tokyo, Japan

CS-747 (prasugrel, LY640315) is a novel thienopyridine oral antiplatelet agent with selective in vivo P2Y₁₂ receptor inhibitory activity. Our previous studies have shown that oral administration of CS-747 to rats resulted in an approximately 10-fold more potent inhibitory effect on adenosine 5'-diphosphate (ADP)-induced ex vivo platelet aggregation and on thrombus formation compared to clopidogrel. Several lines of evidence suggest that CS-747's potent effect is dependent on its active metabolite. In the present study, in vitro effects of R-99224 (a component of R-138727, CS-747's active metabolite) were compared to those of clopidogrel's active metabolite. In washed rat platelets, R-99224 inhibited platelet aggregation induced by ADP (10 µM) and 2-MeS-ADP (0.1 µM) with IC₅₀ values of 1.8 µM and 1.2 µM, respectively. Clopidogrel's active metabolite also inhibited platelet aggregation by both agonists with IC₅₀ values of 2.4 µM and 1.4 µM, respectively, indicating similar potency of both compound's active metabolites. We further evaluated the effects of both active metabolites on ADP binding and signal transduction in platelets. Both active metabolites partially but significantly inhibited [³H]-2-MeS-ADP binding to rat platelets in the same concentration range (0.03–30 µM). In addition, the effect of R-99224 on ADP (10 µM)-induced decrease in PGE₁-stimulated intraplatelet cAMP levels, whose decrease is mediated by P2Y₁₂ receptors, was examined in rats. Pretreatment of platelets with either active metabolite (0.3–3 µM) showed no significant effect on basal or PGE₁ (10 µM)-stimulated cAMP levels but both neutralized the ADP-induced decrease in cAMP levels at similar concentrations. Taken together, these results indicate that the active metabolites of the two thienopyridines, while structurally distinct, have similar P2Y₁₂ receptor antagonistic activities in vitro despite the 10-fold greater antiplatelet and antithrombotic potency of CS-747 in vivo.