Clopidogrel and Ticlopidine: P2Y₁₂Adenosine Diphosphate-Receptor Antagonists for the Prevention of Atherothrombosis

Abstract

Ticlopidine and clopidogrel belong to the same chemical family of thienopyridine adenosine diphosphate (ADP)-receptor antagonists. They have shown their efficacy as platelet antiaggregant and antithrombotic agents in many animal models, both ex vivo and in vivo. Although ticlopidine was discovered more than 30 years ago, it was only recently that the mechanism of action of ADP-receptor antagonists was characterized in detail. Ticlopidine and clopidogrel both behave in vivo as specific antagonists of P2Y (12), one of the ADP receptors on platelets. Metabolic steps that involve cytochrome P450-dependent pathways are required to generate the active metabolite responsible for this in vivo activity. The active moiety is a reactive thiol derivative that targets P2Y (12) on platelets. The interaction is irreversible, accounting for the observation that platelets are definitely antiaggregated, even if no active metabolite is detectable in plasma. The interaction is specific for P2Y (12); other purinoceptors such as P2Y (1) and P2Y (13) are spared. This results in inhibition of the binding of the P2Y (12) agonist 2-methylthio-ADP and the ADP-induced downregulation of adenylyl cyclase. Platelet aggregation is affected not only when triggered by ADP but also by aggregation inducers when used at concentrations requiring released ADP as an amplifier. The efficacy and safety of clopidogrel has been established in several large, randomized, controlled trials. The clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE) trial demonstrated the superiority of clopidogrel over acetylsalicylic acid (ASA) in patients at risk of ischemic events, including ischemic stroke, myocardial infarction (MI), and peripheral arterial disease. The clopidogrel in unstable angina to prevent recurrent ischemic events (CURE) trial showed a sustained, incremental benefit when clopidogrel was added to standard therapy (including ASA) in patients with unstable angina and non-Q-wave MI. The clopidogrel for the reduction of events during observation (CREDO) trial demonstrated the benefit of continuing clopidogrel (plus ASA) for 12 months, as opposed to 1 month, after percutaneous coronary intervention. The proven efficacy of clopidogrel, coupled with its favorable safety and tolerability profile, has prompted its evaluation in an extensive, ongoing clinical trial program that will help to further characterize the benefit of clopidogrel in patients with a range of atherothrombotic profiles.

Inhibition of the platelet P2Y12 receptor for adenosine diphosphate potentiates the antiplatelet effect of prostacyclin

“…It is well known that pharmacologic inhibition of P2Y 12 with the thienopyriridine compounds ticlopidine and clopidogrel has a very good antithrombotic effect in patients at risk of cardiovascular or cerebrovascular disease [15,16]. In some clinical trials, the antithrombotic effect of these drugs proved to be superior, albeit marginally, to that of aspirin [33,34], despite the fact that thienopyridines do not adequately inhibit their pharmacological target in a relatively high percentage of treated patients [16], as opposed to aspirin, which adequately inhibits the activity of cyclooxygenase-1 (COX-1), which is its pharamacologic target [16], in the vast majority of treated patients [35][36][37].…”

“…In fact, P2Y 12 is the target of potent antithrombotic drugs: its irreversible inhibition by the thienopyridine drugs ticlopidine or clopidogrel effectively reduces the incidence of cardiovascular events in patients at risk [15,16]. New, promising anti-P2Y 12 drugs, such as the thienopyridine prasugrel and the direct, reversible P2Y 12 antagonists cangrelor and AZD6140, are currently under clinical development [17,18].…”

P2 receptors and platelet function

“…This was due to the fact that the potent antithrombotic thienopyridine compounds ticlopidine and clopidogrel, of which an active liver metabolite selectively and irreversibly targets the P2Y 12 receptor, were used as molecular tools to characterize platelet responses to ADP and the role of the latter in thrombosis [106]. The thienopyridine compounds are prodrugs which have to be metabolized by the liver in order to generate active metabolites.…”

“…Large-scale clinical trials have demonstrated the beneficial effects of thienopyridines in the prevention of major cardiac events after coronary artery stent insertion and in the secondary prevention of major vascular events in patients with a history of cerebrovascular, coronary or peripheral artery disease [106,112].…”

Deuterated Clopidogrel Analogues as a New Generation of Antiplatelet Agents

“…KEYWORDS: Clopidogrel resistance, clinical variability, prodrug attrition, piperidine deuteration, targeted metabolic shift, bioactivation potentiation C lopidogrel (CPG) is a thienopyridine antiplatelet prodrug that has been widely used in the treatment of cardiovascular diseases, including atherothrombosis, unstable angina, and myocardial infarction. 1 As shown in Scheme 1, CPG (M0) is activated through a two-step cytochrome P450 (CYP)-catalyzed process to form its active metabolite (M13). 2,3 Despite being one of the most prescribed cardiovascular medications of the past decade, CPG is associated with a high clinical uncertainty for its antithrombotic therapy.…”