Pharmacology of emerging novel platelet inhibitors

Chemical structures of antiplatelet agents. Shown here are the chemical structures of 6 established and emerging antiplatelet agents. Ticlopidine, clopidogrel, and prasugrel are first, second, and third-generation thienopyridines, respectively, that irreversibly inhibit the P2Y₁₂ receptor. AZD6140 is a cyclopentyltriazolopyrimidine that reversibly inhibits the P2Y₁₂ receptor. Cangrelor is an ATP analog that reversibly inhibits the P2Y₁₂ receptor. SCH 530348 is a TRA that reversibly inhibits PAR-1.

Molecular targets of established and emerging antiplatelet therapies. Thrombin binds to its cognate receptor, PAR-1, on platelets, which leads to shape change, granule secretion (including the extracellular release of ADP, which interacts with its platelet receptors to augment thrombin activity), thromboxane A₂ (TXA₂) generation, and activation of the glycoprotein (GP) IIb/IIIa receptor, resulting in sustained platelet aggregation. Protease-activated receptor 1, a 7-transmembrane serpentine receptor, is linked to G_q-and G_i-coupled signaling pathways that mediate platelet function. SCH 530348 is a selective PAR-1 receptor antagonist that abrogates thrombin-induced platelet activation and aggregation. Aspirin irreversibly inhibits cyclooxygenase (COX)-1, which catalyzes the production of TXA₂, a potent platelet aggregator, generated by platelets activated by thrombin and other agonists (eg, ADP). Adenosine 5′-diphosphate binds to its 7-transmembrane serpentine receptors, P2Y₁ and P2Y₁₂, to activate platelets. P2Y₁ is coupled to G_q and G₁₂, and G_q is linked to a signaling pathway involving phospholipase C (PLC) activation, resulting in a rise in the intracellular calcium concentration ([Ca⁺²]_i) and protein kinase C (PKC) activation, leading to GP IIb/IIIa activation and transient platelet aggregation. The P2Y₁-coupled G₁₂ signaling pathway mediates platelet shape change. P2Y₁₂ is linked to G_i-coupled signaling cascades associated with adenylcyclase down-regulation and decreased cyclic-3′,5′-monophosphate (cAMP) production, which mediates GP IIb/IIIa receptor activation, leading to sustained platelet aggregation and a pathway that triggers augmentation of granule secretion and TXA₂ generation and GP IIb/IIIa receptor activation. Adenosine 5′-triphosphate activates the P2X₁ receptor, which triggers calcium movement associated with platelet shape change. The prodrugs clopidogrel and prasugrel are metabolized by the hepatic CYP system to active metabolites that are selective P2Y₁₂ receptor antagonists that block ADP-induced platelet activation. AZD6140, a reversible P2Y₁₂ antagonist, and cangrelor, an ATP analog, are selective P2Y₁₂ receptor antagonists that block ADP-stimulated platelet aggregation. The binding of fibrinogen to activated GP IIb/IIIa receptors on adjacent platelets is the final common pathway for platelet aggregation and thrombus formation. Intravenous abciximab, eptifibatide, and tirofiban are selective GP IIb/IIIa receptor antagonists that block the GP IIb/IIIa receptor–fibrinogen interaction and thereby mitigate platelet aggregation.

Primary metabolic pathways for prasugrel and clopidogrel. A significant portion (approximately 85%) of the administered dose of clopidogrel is deactivated in the early stages of its metabolism by esterases to a carboxylic acid derivative, SR26334, resulting in less availability of the active metabolite. A 2-step process that is mainly CYP3A4-dependent catalyzes the conversion of clopidogrel to 2-oxo-clopidogrel, which is then transformed to the clopidogrel active metabolite. Prasugrel is rapidly hydrolyzed by carboxyesterases to a lactone, R-95913, which is then converted to its active metabolite, R-138727, by multiple CYP isotypes. Thus, there is a more efficient metabolic conversion of prasugrel into its active metabolite, which yields concentrations 10-fold to 100-fold higher than that of clopidogrel. The active metabolites of both prasugrel and clopidogrel covalently bind to the active site of the P2Y₁₂ receptor in a similar manner through a disulfide linkage.