• Thomas Gremmel, Ivan B Yanachkov, Milka I Yanachkova, George E Wright, Joseph Wider, Vishnu V R Undyala, Alan D Michelson, Andrew L Frelinger, and Karin Przyklenk.
• From the Center for Platelet Research Studies, Division of Hematology/Oncology, Boston Children's Hospital, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA (T.G., A.D.M., A.L.F.); Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria (T.G.); GLSynthesis Inc, Worcester, MA (I.B.Y., M.I.Y., G.E.W.); and Cardiovascular Research Institute and Departments of Physiology and Emergency Medicine, Wayne State University School of Medicine, Detroit, MI (J.W., V.V.R.U., K.P.). thomas.gremmel@meduniwien.ac.at.
• Arterioscler. Thromb. Vasc. Biol. 2016 Mar 1; 36 (3): 501-9.

ObjectiveUnlike 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 ResultsWe 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.ConclusionsSynergistic 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.© 2016 American Heart Association, Inc.

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