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CARDIOVASCULAR

MRS2500 [2-Iodo-N⁶-methyl-(N)-methanocarba-2'-deoxyadenosine-3',5'-bisphosphate], a Potent, Selective, and Stable Antagonist of the Platelet P2Y₁ Receptor with Strong Antithrombotic Activity in Mice

Institut National de la Sante et de la Recherche Medicale, U311, Strasbourg, France; Etablissement Français du Sang-Alsace, Strasbourg, France (B.H., C.N., J.-P.C., F.L., C.G.); University of Strasbourg, Strasbourg, France (B.H., J.-P.C., F.L., C.G.); Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland (E.J.R., K.A.J.); and Unità di Ematologia e Trombosi, Ospedale San Paolo, Dipartimento di Medicina Chirurgia e Odontoiatria, Università di Milano, Milano, Italy (M.C.)

The platelet P2Y₁ ADP receptor is an attractive target for new antiplatelet drugs. However, because of the lack of strong and stable antagonists, only a few studies have suggested that pharmacological inhibition of the P2Y₁ receptor could efficiently inhibit experimental thrombosis in vivo. Our aim was to determine whether the newly described potent and selective P2Y₁ receptor antagonist MRS2500 [2-iodo-N⁶-methyl-(N)-methanocarba-2'-deoxyadenosine-3',5'-bisphosphate] could inhibit platelet function ex vivo and experimental thrombosis in mice in vivo. MRS2500 was injected intravenously into mice, and its effect on ex vivo platelet aggregation and in several models of thrombosis in vivo was determined. MRS2500 displayed high potency and stable and selective P2Y₁ receptor inhibition ex vivo. Although MRS2500 injection resulted in only moderate prolongation of the bleeding time, it provided strong protection in systemic thromboembolism induced by infusion of a mixture of collagen and adrenaline. MRS2500 also potently inhibited localized arterial thrombosis in a model of laser-induced vessel wall injury with two degrees of severity. Moreover, combination of MRS2500 with clopidogrel, the irreversible inhibitor of the platelet P2Y₁₂ receptor for ADP, led to increased antithrombotic efficacy compared with each alone. These results add further evidence for a role of the P2Y₁ receptor in thrombosis and validate the concept that targeting the P2Y₁ receptor could be a relevant alternative or complement to current antiplatelet strategies.

Address correspondence to: Dr. C. Gachet, INSERM U311, Etablissement Français du Sang-Alsace, 10 rue Spielmann, BP 36, 67065 Strasbourg Cédex, France. E-mail: christian.gachet{at}efs-alsace.fr

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