{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T11:12:05Z","timestamp":1791285125183,"version":"4.1.0"},"reference-count":35,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"3","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["ATVB"],"published-print":{"date-parts":[[2016,3]]},"abstract":"<jats:sec>\n                    <jats:title>Objective\u2014<\/jats:title>\n                    <jats:p>\n                      Unlike currently approved adenosine diphosphate receptor antagonists, the new diadenosine tetraphosphate derivative GLS-409 targets not only P2Y\n                      <jats:sub>12<\/jats:sub>\n                      but also the second human platelet adenosine diphosphate receptor P2Y\n                      <jats:sub>1<\/jats:sub>\n                      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.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Approach and Results\u2014<\/jats:title>\n                    <jats:p>\n                      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 P2Y\n                      <jats:sub>1<\/jats:sub>\n                      and P2Y\n                      <jats:sub>12<\/jats:sub>\n                      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 P2Y\n                      <jats:sub>1<\/jats:sub>\n                      inhibitor MRS 2179 on agonist-stimulated platelet aggregation in human platelet-rich plasma and whole blood before and 2 hours after aspirin intake.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions\u2014<\/jats:title>\n                    <jats:p>\n                      Synergistic inhibition of both P2Y\n                      <jats:sub>1<\/jats:sub>\n                      and P2Y\n                      <jats:sub>12<\/jats:sub>\n                      adenosine diphosphate receptors by GLS-409 immediately attenuates platelet-mediated thrombosis and effectively blocks agonist-stimulated platelet aggregation irrespective of concomitant aspirin therapy.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/atvbaha.115.306885","type":"journal-article","created":{"date-parts":[[2016,1,7]],"date-time":"2016-01-07T23:30:42Z","timestamp":1452209442000},"page":"501-509","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":56,"title":["Synergistic Inhibition of Both P2Y\n                    <sub>1<\/sub>\n                    and P2Y\n                    <sub>12<\/sub>\n                    Adenosine Diphosphate Receptors As Novel Approach to Rapidly Attenuate Platelet-Mediated Thrombosis"],"prefix":"10.1161","volume":"36","author":[{"given":"Thomas","family":"Gremmel","sequence":"first","affiliation":[{"name":"From the Center for Platelet Research Studies, Division of Hematology\/Oncology, Boston Children\u2019s 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..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivan B.","family":"Yanachkov","sequence":"additional","affiliation":[{"name":"From the Center for Platelet Research Studies, Division of Hematology\/Oncology, Boston Children\u2019s 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..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Milka I.","family":"Yanachkova","sequence":"additional","affiliation":[{"name":"From the Center for Platelet Research Studies, Division of Hematology\/Oncology, Boston Children\u2019s 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..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George E.","family":"Wright","sequence":"additional","affiliation":[{"name":"From the Center for Platelet Research Studies, Division of Hematology\/Oncology, Boston Children\u2019s 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..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph","family":"Wider","sequence":"additional","affiliation":[{"name":"From the Center for Platelet Research Studies, Division of Hematology\/Oncology, Boston Children\u2019s 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..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vishnu V.R.","family":"Undyala","sequence":"additional","affiliation":[{"name":"From the Center for Platelet Research Studies, Division of Hematology\/Oncology, Boston Children\u2019s 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..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alan D.","family":"Michelson","sequence":"additional","affiliation":[{"name":"From the Center for Platelet Research Studies, Division of Hematology\/Oncology, Boston Children\u2019s 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..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"III","given":"Andrew L.","family":"Frelinger","sequence":"additional","affiliation":[{"name":"From the Center for Platelet Research Studies, Division of Hematology\/Oncology, Boston Children\u2019s 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..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karin","family":"Przyklenk","sequence":"additional","affiliation":[{"name":"From the Center for Platelet Research Studies, Division of Hematology\/Oncology, Boston Children\u2019s 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..."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.ATV.0000145980.39477.a9"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehr373"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehv320"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa010746"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa0706482"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa0904327"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1500857"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehi851"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.273.4.2030"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2004-02-0534"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.95.14.8070"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjp.0704673"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2005.03.009"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.73.11.3984"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/0006-291X(83)90997-X"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.ATV.0000075913.00428.FD"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.94.8.4034"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.89.6.2370"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.thromres.2009.11.006"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1111\/jth.12035"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2015.10.055"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.97.7.692"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.thromres.2007.07.002"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1538-7836.2009.03693.x"},{"key":"e_1_3_4_27_2","first-page":"IV3","article-title":"An in vivo model of experimental arterial stenosis, intimal damage, and periodic thrombosis.","volume":"83","author":"Folts J","year":"1991","unstructured":"Folts J. 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