Synergistic Inhibition of Both P2Y1 and P2Y12 Adenosine Diphosphate Receptors As Novel Approach to Rapidly Attenuate Platelet-Mediated Thrombosis

• Published in: Arteriosclerosis, thrombosis, and vascular biology Vol. 36; no. 3; pp. 501 - 509
• Main Authors: Gremmel, Thomas, Yanachkov, Ivan B., Yanachkova, Milka I., Wright, George E., Wider, Joseph, Undyala, Vishnu V.R., Michelson, Alan D., Frelinger, Andrew L., Przyklenk, Karin
• Format: Journal Article
• Language: English
• Published: United States American Heart Association, Inc 01.03.2016
• Subjects: Adenosine Diphosphate - analogs & derivatives; Adenosine Diphosphate - pharmacology; Adenosine Monophosphate - analogs & derivatives; Adenosine Monophosphate - pharmacology; Adult; Animals; Aspirin - pharmacology; Blood Coagulation - drug effects; Blood Platelets - drug effects; Blood Platelets - metabolism; Coronary Thrombosis - blood; Coronary Thrombosis - drug therapy; Dinucleoside Phosphates - pharmacology; Disease Models, Animal; Dogs; Dose-Response Relationship, Drug; Female; Fibrinolytic Agents - pharmacology; Humans; Male; Platelet Aggregation - drug effects; Platelet Aggregation Inhibitors - pharmacology; Platelet Function Tests; Purinergic P2Y Receptor Antagonists - pharmacology; Rats, Sprague-Dawley; Receptors, Purinergic P2Y1 - blood; Receptors, Purinergic P2Y1 - drug effects; Receptors, Purinergic P2Y12 - blood; Receptors, Purinergic P2Y12 - drug effects; Time Factors; Young Adult; aspirin; antiplatelet therapy; adenosine diphosphate; P2Y12; P2Y1
• ISSN: 1079-5642; 1524-4636; 1524-4636
• DOI: 10.1161/ATVBAHA.115.306885

OBJECTIVE—Unlike currently approved adenosine diphosphate receptor antagonists, the new diadenosine tetraphosphate derivative GLS-409 targets not only P2Y12 but also the second human platelet adenosine diphosphate receptor P2Y1 and may, therefore, be a promising antiplatelet drug candidate. The current study is the first to investigate the in vivo antithrombotic effects of GLS-409. APPROACH AND RESULTS—We studied (1) the in vivo effects of GLS-409 on agonist-stimulated platelet aggregation in anesthetized rats, (2) the antithrombotic activity of GLS-409 and the associated effect on the bleeding time in a canine model of platelet-mediated coronary artery thrombosis, and (3) the inhibition of agonist-stimulated platelet aggregation by GLS-409 versus selective P2Y1 and P2Y12 inhibition in vitro in samples from healthy human subjects before and 2 hours after aspirin intake. In vivo treatment with GLS-409 significantly inhibited adenosine diphosphate- and collagen-stimulated platelet aggregation in rats. Further, GLS-409 attenuated cyclic flow variation, that is, platelet-mediated thrombosis, in vivo in our canine model of unstable angina. The improvement in coronary patency was accompanied by a nonsignificant 30% increase in bleeding time. Of note, GLS-409 exerted its effects without affecting rat and canine hemodynamics. Finally, in vitro treatment with GLS-409 showed effects similar to that of cangrelor and the combination of cangrelor with the selective P2Y1 inhibitor MRS 2179 on agonist-stimulated platelet aggregation in human platelet-rich plasma and whole blood before and 2 hours after aspirin intake. CONCLUSIONS—Synergistic inhibition of both P2Y1 and P2Y12 adenosine diphosphate receptors by GLS-409 immediately attenuates platelet-mediated thrombosis and effectively blocks agonist-stimulated platelet aggregation irrespective of concomitant aspirin therapy.