Current and Novel Antiplatelet Therapies for the Treatment of Cardiovascular Diseases

Figures

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  Figure 1. Major signaling events and responses in resting and activated platelets. Under physiological conditions, endothelial cells release nucleotidases that degrade adenosine di- and tri-phosphate (ADP and ATP, respectively) to adenosine. They also secrete prostacyclin (also known as prostaglandin I2; PGI2) and nitric oxide (NO). NO and PGI2 as well as adenosine activate within platelets guanylyl (GC) and adenylyl cyclases (AC) respectively, increasing intra-platelet cyclic guanosine and adenosine 3′,5′-monophosphate (cGMP and cAMP, respectively) which are powerful platelet inhibitors maintaining the glycoprotein (GP) IIbIIIa, also called integrin αIIbβ3, in its inactive form. cAMP and cGMP are subsequently hydrolyzed by phosphodiesterases (PDE) limiting their intracellular levels. Following platelet activation, arachidonic acid (AA) produced from membrane phospholipids upon the action of phospholipase A2 is metabolized in thromboxane A2 (TXA2) that activates the Thromboxane Prostanoid (TP) receptor. ADP, by activating P2Y12 receptor, induces an inhibition of the AC that decreases cAMP synthesis. Following coagulation activation, generated thrombin cleaves its receptors on platelet…

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  Figure 2. P2Y12 receptor signaling pathways in platelets. ADP acts as a soluble agonist of P2Y12 receptor. It is a Gi-protein-coupled receptor consisting of a single polypeptide chain of seven transmembrane α helices. Its activation inhibits via the Gαi subunit, the adenylate cyclase-mediated signaling, which decreases the cyclic adenosine 3′,5′-monophosphate (cAMP) levels and results in the dephosphorylation of some cytoskeletal proteins, including vasodilator-stimulated phosphoprotein (VASP). P2Y12 receptor activation also stimulates the phosphoinositide 3-kinase (PI3K) via Gβγ protein complex resulting in Akt stimulation, which activates a number of downstream substrate proteins thereby increasing the cytosolic Ca2+ levels and inducing granule secretion. Both pathways ultimately lead to a conformational change in the glycoprotein (GP) IIbIIIa (also known as integrin αIIbβ3) on the platelet surface, which links fibrinogen, resulting in platelet aggregation.

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  Figure 3. Targets of current and emerging antiplatelet therapies. The currently available antiplatelet drugs (in grey) essentially act by preventing the formation of secondary messengers (cyclooxygenase-1 [COX1] inhibitors), by interacting with intracellular signaling pathways (phosphodiesterases [PDE] inhibitors and the prostacyclin [PGI2] analogue), by blocking membrane receptors (P2Y12 receptor antagonists and the protease-activated receptor PAR1 antagonist), or by inhibiting platelet aggregation (glycoprotein [GP] IIbIIIa inhibitors). Novel antiplatelet drugs in development (in purple) are mainly directed against platelet glycoproteins such as GPVI, GPIbα, and GPIIbIIIa or block membrane receptors such as the 2 purinergic receptors P2Y12 and P2Y1 as well as the receptors PAR1 and PAR4. Other drugs directed against different platelet-activation processes, such as adhesion, signaling and pro-coagulant activity, are also under development.

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  Figure 4. Clopidogrel metabolism pathways. Clopidogrel is extensively metabolized (85%) to a pharmacologically inactive metabolite via intestinal carboxylesterase 1 (CES1) and is eliminated in the urine and feces. The remaining 15% is metabolized by mixed-function oxidase enzymes from the CYP superfamily, first to 2-oxo-clopidogrel via CYP2C19, 1A2, and 2B6, and then to the active metabolite via CYP2C19 and, to a lesser extent, 2C9, 3A4, 3A5, and 2B6.