title: New highly active antiplatelet agents with dual specificity for platelet P2Y1 and P2Y12 adenosine diphosphate receptors.
abstract: Currently approved platelet adenosine diphosphate (ADP) receptor antagonists target only the platelet P2Y12 receptor. Moreover, especially in patients with acute coronary syndromes, there is a strong need for rapidly acting and reversible antiplatelet agents in order to minimize the risk of thrombotic events and bleeding complications. In this study, a series of new P(1),P(4)-di(adenosine-5') tetraphosphate (Ap4A) derivatives with modifications in the base and in the tetraphosphate chain were synthesized and evaluated with respect to their effects on platelet aggregation and function of the platelet P2Y1, P2Y12, and P2X1 receptors. The resulting structure-activity relationships were used to design Ap4A analogs which inhibit human platelet aggregation by simultaneously antagonizing both P2Y1 and P2Y12 platelet receptors. Unlike Ap4A, the analogs do not activate platelet P2X1 receptors. Furthermore, the new compounds exhibit fast onset and offset of action and are significantly more stable than Ap4A to degradation in plasma, thus presenting a new promising class of antiplatelet agents.
authors.affiliation: GLSynthesis, Inc. Worcester, MA, USA. Electronic address: ivan.yanachkov@glsynthesis.com.
authors.forename: Ivan B
authors.initials: IB
authors.lastname: Yanachkov
authors.affiliation: Center for Platelet Function Studies, Department of Pediatrics, University of Massachusetts Medical School, Worcester, MA, USA; Hematology Division, Chang Gung Memorial Hospital, Chang Gung University, Taipei, Taiwan.
authors.forename: Hung
authors.initials: H
authors.lastname: Chang
authors.affiliation: GLSynthesis, Inc. Worcester, MA, USA.
authors.forename: Milka I
authors.initials: MI
authors.lastname: Yanachkova
authors.affiliation: GLSynthesis, Inc. Worcester, MA, USA.
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Dix
authors.affiliation: Center for Platelet Research Studies, Division of Hematology/Oncology, Boston Children's Hospital, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Berny-Lang
authors.affiliation: Center for Platelet Research Studies, Division of Hematology/Oncology, Boston Children's Hospital, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Gremmel
authors.affiliation: Center for Platelet Research Studies, Division of Hematology/Oncology, Boston Children's Hospital, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; Center for Platelet Function Studies, Department of Pediatrics, University of Massachusetts Medical School, Worcester, MA, USA.
authors.forename: Alan D
authors.initials: AD
authors.lastname: Michelson
authors.affiliation: GLSynthesis, Inc. Worcester, MA, USA.
authors.forename: George E
authors.initials: GE
authors.lastname: Wright
authors.affiliation: Center for Platelet Research Studies, Division of Hematology/Oncology, Boston Children's Hospital, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; Center for Platelet Function Studies, Department of Pediatrics, University of Massachusetts Medical School, Worcester, MA, USA.
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Frelinger
mesh_terms: D000818:Animals; D060326:Chemistry Techniques, Synthetic; D015226:Dinucleoside Phosphates / Q000737:chemistry / Q000378:metabolism; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004355:Drug Stability; D006801:Humans; D010975:Platelet Aggregation Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D058920:Purinergic P2X Receptor Antagonists / Q000737:chemistry / Q000494:pharmacology; D058921:Purinergic P2Y Receptor Antagonists / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D058474:Receptors, Purinergic P2X1 / Q000378:metabolism; D058472:Receptors, Purinergic P2Y1 / Q000378:metabolism*; D058925:Receptors, Purinergic P2Y12 / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D015226:Dinucleoside Phosphates; C548576:P2RY12 protein, human; D010975:Platelet Aggregation Inhibitors; D058920:Purinergic P2X Receptor Antagonists; D058921:Purinergic P2Y Receptor Antagonists; D058474:Receptors, Purinergic P2X1; D058472:Receptors, Purinergic P2Y1; D058925:Receptors, Purinergic P2Y12; C020733:diadenosine tetraphosphate
keywords: Acute coronary syndromes; Adenosine diphosphate; Antiplatelet therapy; Antithrombotics; Bis-nucleoside polyphosphates; Cardiovascular disease; Dinucleoside polyphosphates; Inhibitors; P2X1; P2Y(1); P2Y(12); Platelets