Effective Inhibition of Platelet Aggregation and Release Reaction with Lack of Effect on Shape Change by CS-747 (Prasugrel, LY640315) and Its Active Metabolite

Abstract number: P2301

Ogawa¹ T, Sugidachi¹ A, Isobe¹ T, Shimoji¹ T, Suzuki¹ N, Maeda² N, Matsushita² Y, Jakubowski³ JA, Asai¹ F

¹¹Pharmacology and Molecular Biology Research Laboratories, Sankyo Co. Ltd., Tokyo, Japan ¹¹Pharmacology and Molecular Biology Research Laboratories, Sankyo Co. Ltd., Tokyo, Japan ²²Medicinal Safety Research Laboratories, Sankyo Co. Ltd., Tokyo, Japan ³³Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, USA

Previous studies have demonstrated that CS-747 (prasugrel, LY640315), which is metabolized in vivo to an active metabolite with P2Y₁₂ antagonist activity, results in potent ex vivo inhibition of ADP-induced platelet aggregation. In the present study, we examined the effects of CS-747 and its active metabolite on ADP-induced platelet shape change and release reaction. Oral administration of CS-747 (1 and 3 mg/kg) to rats (doses previously shown to inhibit platelet aggregation) showed no significant effect on ADP-induced shape change. The active metabolite also had no significant activity on ADP-induced shape change in washed human platelets, although A3P5PS (3–300 µM), a P2Y₁ antagonist, inhibited the shape change. Morphological examination using scanning electron microscope further confirmed lack of activity of the active metabolite on platelet shape change, suggesting little, if any, P2Y₁ antagonistic activity of the active metabolite of CS-747. Effects of the active metabolite on ADP-induced release reaction in human platelets were also examined. Addition of ADP (0.3–30 µM) to human platelet-rich plasma with stirring caused platelet aggregation and extensive release of platelet-derived growth factor (PDGF) and b-thromboglobulin (b-TG). In contrast to the findings from the shape change study, pretreatment with the active metabolite (1–100 µM) resulted in a concentration-related inhibition of both platelet aggregation and release of PDGF and b-TG. The IC₅₀ values for platelet aggregation, PDGF release and b-TG release were 14, 2.5 and 2.7 µM, respectively. These results show that the active metabolite potently inhibits ADP-induced release reaction and aggregation in human platelets. The potent inhibitory effect of the active metabolite of CS-747 on ADP-induced release reaction would be expected to contribute to inhibition of platelet recruitment during thrombus formation. CS-747 represents a novel antiplatelet agent for the prevention of ischemic events in patients with atherothrombotic disease.