ABSTRACT Oral antiplatelet therapy with P2Y(12) receptor blockers (especially clopidogrel) is the current choice of treatment during acute coronary syndromes and percutaneous interventions. To address the various limitations of thienopyridine therapy (including response variability and non-responsiveness) a novel drug, AZD6140, is under clinical development. AZD6140 is an oral and reversible P2Y(12) receptor blocker that does not require hepatic conversion to an active metabolite and produces an overall superior ADP-induced platelet inhibition with less response variability than clopidogrel. It has fast onset and offset actions that may be advantageous in patients who may have to undergo immediate surgery.
Article: ADP Receptor Antagonism[Show abstract] [Hide abstract]
ABSTRACT: ADP is one of the most important mediators of both physiologic hemostasis and thrombosis. Development and utilization of agents that block ADP receptors on the platelet membrane, namely thienopyridines, has represented a major advancement for treatment of patients undergoing percutaneous coronary interventions and those with acute coronary syndromes. Currently, clopidogrel, a second-generation thienopyridine that inhibits the ADP P2Y12 receptor, represents the treatment of choice, in addition to aspirin, for the prevention of stent thrombosis. Further, long-term adjunctive use of this ADP P2Y12 receptor antagonist is also associated with improved clinical outcomes in high-risk patients, and represents the standard of care for these patients. Despite the unambiguous clinical benefit associated with clopidogrel, accumulating experience with this drug has also led to identification of some of its drawbacks, which are related to inadequate platelet inhibition with standard dosage regimens as well as to its irreversible antiplatelet effects. This has led to the questioning of currently recommended clopidogrel dosage regimens as well as to the development of novel and more potent ADP P2Y12 receptor antagonists, some of which are also reversible agents. Numerous studies are currently ongoing with the objective of demonstrating how more potent platelet inhibition using higher loading and maintenance dose regimens of clopidogrel or novel ADP P2Y12 receptor antagonists — such as prasugrel, ticagrelor (AZD 6140) and cangrelor — will affect clinical outcomes. This article reviews the current knowledge of platelet ADP P2Y12 receptor antagonism and the projected developments in this field.American Journal of Cardiovascular Drugs 01/2007; 7(6). DOI:10.2165/00129784-200707060-00005 · 2.20 Impact Factor
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ABSTRACT: Two distinct G protein-coupled purinergic receptors, P2Y1 and P2Y12, mediate ADP driven platelet activation. The clinical effectiveness of P2Y12 blockade is well established. Recent preclinical data suggest that P2Y1 and P2Y12 inhibition provide equivalent antithrombotic efficacy, while targeting P2Y1 has the potential for reduced bleeding liability. In this account, the discovery of a 2-(phenoxypyridine)-3-(phenyl)urea chemotype that inhibited ADP-mediated platelet aggregation in human blood samples is described. Optimization of this series led to the identification of compound 16, 1-(2-(2-tert-butylphenoxy)pyridin-3-yl)-3-4-(trifluoromethoxy)phenylurea, which demonstrated a 68 ± 7% thrombus weight reduction in an established rat arterial thrombosis model (10 mg/kg plus 10 mg/kg/h) while only prolonging cuticle and mesenteric bleeding times by 3.3- and 3.1-fold, respectively in provoked rat bleeding time models. These results suggest that a P2Y1 antagonist could potentially provide a safe and efficacious antithrombotic profile.Journal of Medicinal Chemistry 01/2013; 56(4). DOI:10.1021/jm301708u · 5.48 Impact Factor
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ABSTRACT: Antiplatelet therapy is a mainstay in the treatment of patients who have undergone percutaneous coronary intervention (PCI). Although the 2007 PCI treatment guidelines were published by the American College of Cardiology, the American Heart Association, and the Society for Cardiovascular Angiography and Interventions, new clinical evidence has emerged, expanding our understanding of antiplatelet use and potentially affecting the treatment guidelines. For example, clinical trial results prompted a Science Advisory to recommend that dual therapy with aspirin and clopidogrel be used for longer periods—up to 1 year in patients who receive bare metal stents and at least 1 year in patients receiving drug-eluting stents. New trial results have also emerged regarding the use of glycoprotein IIb/IIIa antagonists such as abciximab, eptifibatide, and tirofiban. This article reviews the current recommendations for antiplatelet therapy in PCI patients, recent trial results, newly developed agents, ongoing clinical trials, and the future direction of antiplatelet therapy in patients who undergo PCI. © 2009 Wiley-Liss, Inc.Catheterization and Cardiovascular Interventions 10/2009; 74(4):579 - 597. DOI:10.1002/ccd.22021 · 2.51 Impact Factor