title: The P2Y(1) receptor as a target for new antithrombotic drugs: a review of the P2Y(1) antagonist MRS-2179.
abstract: MRS-2179 is a selective P2Y(1) receptor antagonist, a strong inhibitor of ADP-induced platelet aggregation in vitro and ex vivo. By i.v. administration to mice MRS-2179 increases resistance to thromboembolism induced by a mixture of collagen and epinephrine or by a tissue factor. Likewise, it significantly increases the time to thrombus formation in a ferric chloride-induced model of localized arterial thrombosis. MRS-2179 also confers resistance to localized venous thrombosis, which is dependent on thrombin generation and in which platelets play a relatively minor role as compared to stasis or activation of coagulation. These data provide considerable encouragement for the development of new P2Y(1) receptor antagonists. Nevertheless, the properties of MRS-2179 indicate that new compounds should be optimized in order to increase the half-life of the molecule in vivo and its selectivity and potency at the P2Y(1) receptor. Further directions include the synthesis of molecules with modifications of the nucleotide structure which replace the fragile moiety by a stable bond and should lead to a non-hydrolysable structure. In conclusion, P2Y(1) antagonists have been shown to be efficient antithrombotic agents. MRS-2179 is the first P2Y(1) antagonist with antithrombotic action. Its effectiveness demonstrates that the P2Y(1) receptor is a potentially promising target for drugs designed to treat thrombotic syndromes.
authors.affiliation: INSERM U.311, Laboratoire de Biologie et de Pharmacologie de l'Hémostase et de la Thrombose, Etablissement Français du Sang-Alsace, Strasbourg, France.
authors.forename: Anthony
authors.initials: A
authors.lastname: Baurand
authors.forename: Christian
authors.initials: C
authors.lastname: Gachet
mesh_terms: D000244:Adenosine Diphosphate / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D005343:Fibrinolytic Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D010974:Platelet Aggregation / Q000187:drug effects; D058919:Purinergic P2 Receptor Antagonists; D058472:Receptors, Purinergic P2Y1; D013927:Thrombosis / Q000188:drug therapy
chemical_list: D005343:Fibrinolytic Agents; C111914:N(6)-methyl-2'-deoxyadenosine 3',5'-diphosphate; C546382:P2RY1 protein, human; C546383:P2ry1 protein, mouse; D058919:Purinergic P2 Receptor Antagonists; D058472:Receptors, Purinergic P2Y1; D000244:Adenosine Diphosphate