title: Preclinical and clinical studies with selective reversible direct P2Y12 antagonists.
abstract: 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.
authors.affiliation: Department of Integrative Pharmacology, AstraZeneca Mölndal, Pepparedsleden 1, S-431 83 Mölndal, Sweden. Hans.vanGiezen@astrazeneca.com
authors.forename: J J J
authors.initials: JJ
authors.lastname: van Giezen
authors.forename: Robert G
authors.initials: RG
authors.lastname: Humphries
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D000244:Adenosine Diphosphate / Q000494:pharmacology; D000249:Adenosine Monophosphate / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D000284:Administration, Oral; D000818:Animals; D001157:Arterial Occlusive Diseases / Q000188:drug therapy; D002986:Clinical Trials as Topic; D004285:Dogs; D004311:Double-Blind Method; D004353:Drug Evaluation, Preclinical; D005260:Female; D005343:Fibrinolytic Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D008565:Membrane Proteins / Q000037:antagonists & inhibitors*; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D058919:Purinergic P2 Receptor Antagonists; D011725:Pyridines / Q000494:pharmacology; D011817:Rabbits; D016032:Randomized Controlled Trials as Topic; D058925:Receptors, Purinergic P2Y12; D013927:Thrombosis / Q000188:drug therapy; D000077486:Ticagrelor
chemical_list: C503701:AR C109318XX; D005343:Fibrinolytic Agents; D008565:Membrane Proteins; C548576:P2RY12 protein, human; D010975:Platelet Aggregation Inhibitors; D058919:Purinergic P2 Receptor Antagonists; D011725:Pyridines; D058925:Receptors, Purinergic P2Y12; C446540:thienopyridine; D000249:Adenosine Monophosphate; D000244:Adenosine Diphosphate; C117446:cangrelor; D000077486:Ticagrelor; D000241:Adenosine