Pharmacology of CS-747 (prasugrel, LY640315), a Novel, Potent Antiplatelet Agent with in Vivo P2Y₁₂Receptor Antagonist Activity

Abstract

CS-747 (prasugrel, LY640315) is a member of the thienopyridine class of oral platelet aggregation inhibitors that includes ticlopidine and clopidogrel. A single oral administration of CS-747 produced a dose-related inhibition of platelet aggregation in rats that was approximately 10- and 100-fold more potent than that of clopidogrel and ticlopidine, respectively. The antiaggregatory effect of CS-747 was evident at 30 minutes and lasted until 72 hours after dosing, indicating fast onset and long duration of action. CS-747 showed more potent antithrombotic activity compared with clopidogrel and ticlopidine with the same rank order as the antiaggregatory potencies. Combined administration of CS-747 with aspirin to rats produced substantially greater inhibition of both platelet aggregation and thrombus formation compared with each agent alone. The antiplatelet action of CS-747 is due to irreversible and selective blockade of platelet P2Y (12) adenosine diphosphate (ADP) receptors by its active metabolite R-138727. In phase I studies, a single oral dose of CS-747 (30 and 75 mg) produced > 50% inhibition of ADP-induced platelet aggregation, with rapid onset (1 hour) and long duration (> 48 hours) of action. In healthy volunteers, once-daily administration of 10 mg CS-747 for 10 days showed significant cumulative inhibition of platelet aggregation from 2 days after the first dose until at least 2 days after the final dose. Studies conducted to date indicate that CS-747 is a highly effective antiplatelet and antithrombotic agent and is anticipated to be effective in the treatment of atherothrombotic and other ischemic vascular diseases.

A multiple dose study of prasugrel (CS‐747), a novel thienopyridine P2Y12 inhibitor, compared with clopidogrel in healthy humans

“…Preclinical studies indicate that like clopidogrel, prasugrel is a prodrug that requires metabolic conversion to an active metabolite [19]. Following oral dosing of prasugrel, there is a rapid and potent inhibition of ADP-induced platelet activation and aggregation [19,22,23]. These early studies demonstrated that the dose required to achieve a given degree of platelet inhibition or inhibition of thrombus formation in preclinical models was approximately one-tenth and one-hundredth that of clopidogrel and ticlopidine, respectively.…”

“…More recently, a novel thienopyridine P2Y 12 inhibitor, prasugrel (CS-747, LY640315), has been identified and profiled [19][20][21][22][23]. Preclinical studies indicate that like clopidogrel, prasugrel is a prodrug that requires metabolic conversion to an active metabolite [19].…”

Pharmacokinetics and pharmacodynamics of single and multiple doses of prasugrel in healthy native Chinese subjects

“…Prasugrel is a thienopyridine adenosine diphosphate (ADP) receptor antagonist prodrug that rapidly converts to an inactive metabolite (R-95913) by carboxyesterase and cannot be detected in plasma. The conversion of R-95913 to R-138727 is catalyzed by cytochrome P450 enzymes ( Figure 1); R-138727 binds specifically and irreversibly to the P2Y 12 ADP receptor and inhibits platelet activation and aggregation for the remainder of the life of the platelet [2] .…”

Prasugrel, a Platelet P2Y 12 Receptor Antagonist, Improves Abnormal Gait in a Novel Murine Model of Thrombotic Hindlimb Ischemia

“…Further studies are therefore required to better understand the role for P2Y 12 inhibition in controlling ischemic limb complications in patients with PAD. Prasugrel, a third‐generation thienopyridine antiplatelet agent used clinically to treat patients with acute coronary syndrome who are undergoing percutaneous coronary intervention,13 has been shown to provide effective inhibition of platelet activation and aggregation via the selective inhibition of platelet P2Y 12 14, 15. Furthermore, it has also been shown to be more potent and consistent than clopidogrel for P2Y 12 inhibition 16.…”