RESUMEN
Starting from adenosine triphosphate (ATP), the identification of a novel series of P2Y(12) receptor antagonists and exploitation of their SAR is described. Modifications of the acidic side chain and the purine core and investigation of hydrophobic substituents led to a series of neutral molecules. The leading compound, 17 (AZD6140), is currently in a large phase III clinical trial for the treatment of acute coronary syndromes and prevention of thromboembolic clinical sequelae.
Asunto(s)
Adenosina Trifosfato/uso terapéutico , Adenosina/análogos & derivados , Proteínas de la Membrana/antagonistas & inhibidores , Antagonistas del Receptor Purinérgico P2 , Trombosis/prevención & control , Adenosina/uso terapéutico , Administración Oral , Animales , Humanos , Receptores Purinérgicos P2Y12 , TicagrelorRESUMEN
An important role for adenosine diphosphate (ADP)-induced platelet activation and aggregation was proposed more than 40 years ago. The clinical use of clopidogrel, a prodrug of an irreversible P2Y (12) antagonist, has further proved the relevance of inhibiting signaling via the platelet-specific P2Y (12) ADP receptor in the prevention of cardiovascular events. Pharmacological studies at AstraZeneca R&D Charnwood have identified direct, selective, and competitive P2Y (12) antagonists, including cangrelor (also known as AR-C69931MX), which is suitable for intravenous administration, and AZD6140, which is suitable for oral administration. In preclinical use, these compounds predictably and effectively inhibited platelet aggregation without significant increases in bleeding time. In clinical use, these compounds may have significant advantages over current antiplatelet agents. This article summarizes preclinical and clinical data on cangrelor and AZD6140 and discusses the potential of these compounds as novel antiplatelet therapies.
Asunto(s)
Adenosina Monofosfato/análogos & derivados , Fibrinolíticos/uso terapéutico , Proteínas de la Membrana/antagonistas & inhibidores , Inhibidores de Agregación Plaquetaria/uso terapéutico , Antagonistas del Receptor Purinérgico P2 , Adenosina/análogos & derivados , Adenosina/química , Adenosina/farmacología , Adenosina Difosfato/farmacología , Adenosina Monofosfato/administración & dosificación , Adenosina Monofosfato/química , Adenosina Monofosfato/farmacología , Adenosina Monofosfato/uso terapéutico , Administración Oral , Animales , Arteriopatías Oclusivas/tratamiento farmacológico , Ensayos Clínicos como Asunto , Perros , Método Doble Ciego , Evaluación Preclínica de Medicamentos , Femenino , Fibrinolíticos/administración & dosificación , Fibrinolíticos/farmacología , Humanos , Inyecciones Intravenosas , Masculino , Agregación Plaquetaria/efectos de los fármacos , Inhibidores de Agregación Plaquetaria/administración & dosificación , Inhibidores de Agregación Plaquetaria/farmacología , Piridinas/farmacología , Conejos , Ensayos Clínicos Controlados Aleatorios como Asunto , Receptores Purinérgicos P2Y12 , Trombosis/tratamiento farmacológico , TicagrelorRESUMEN
OBJECTIVE: Reperfusion therapy for myocardial infarction is limited by a significant reocclusion rate and less optimal myocardial tissue perfusion due to excessive platelet accumulation and recruitment at the sites of vascular injury. We assessed the influence of a selective P2Y(12)-receptor antagonist (AR-C69931MX), in conjunction with thrombolytic therapy, on the prevention of platelet aggregation and thrombus formation. METHODS AND RESULTS: A canine coronary electrolytic injury thrombosis model was used. Tissue-type plasminogen activator (t-PA; 1 mg/kg in phase I, 0.5 mg/kg in phase II in the AR-C69931MX group, and 1 mg/kg in the placebo group in phase I and II) was administered 30 minutes after thrombus formation; either saline or AR-C69931MX (4 micro g x kg(-1) x min(-1)) was given to all animals intravenously 10 minutes before t-PA administration for a total of 2 hours. All animals received heparin (80 U/kg) as an intravenous bolus followed by a continuous infusion of 17 U x kg(-1) x h(-1). Myocardial tissue perfusion was evaluated by use of the colored microsphere technique and real-time myocardial contrast echocardiography. The incidences of reocclusion and cyclic flow variation were significantly decreased in the AR-C69931MX group (P<0.05). Myocardial tissue flow with AR-C69931MX treatment improved significantly at 20 and 120 minutes after reflow, whereas tissue flow with placebo remained at a level similar to that during occlusion (P<0.05). CONCLUSIONS: The adjunctive administration of AR-C69931MX blocked ADP-mediated platelet aggregation and recruitment and prevented platelet-mediated thrombosis, resulting in prolongation of reperfusion time and a decrease in reocclusion and cyclic flow variations. Importantly, myocardial tissue perfusion was significantly improved in the P2Y(12) antagonist group.