{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:24:02Z","timestamp":1787027042745,"version":"build-2736575974"},"reference-count":36,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,6,24]],"date-time":"2025-06-24T00:00:00Z","timestamp":1750723200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Bleeding is the inherent adverse effect of antiplatelet drugs that has limited their use in the prevention of secondary heart attack and stroke. Thus, finding a novel antiplatelet drug with antithrombotic activities while preserving hemostatic function remains a crucial issue. Here, we screened naphthalimide derivatives that we previously synthesized and identified a novel derivative compound\n                      <jats:bold>6<\/jats:bold>\n                      , which has a more potent antithrombotic effect and has no effect on bleeding cessation. This study is aimed to determine the antiplatelet mechanism of compound\n                      <jats:bold>6<\/jats:bold>\n                      and further test whether compound\n                      <jats:bold>6<\/jats:bold>\n                      is a safer and more potent antithrombotic agent.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Platelet aggregation, flow cytometry and immunoblotting were used to determine the\n                      <jats:italic>in vitro<\/jats:italic>\n                      antiplatelet effect of compound\n                      <jats:bold>6<\/jats:bold>\n                      . The study of thrombus formation of mesenteric venules in mice was used to evaluate the antithrombotic effect of compound\n                      <jats:bold>6<\/jats:bold>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Compound\n                      <jats:bold>6<\/jats:bold>\n                      selectively inhibited collagen-mediated platelet aggregation and markedly prevented thrombus formation without bleeding tendency. Compound\n                      <jats:bold>6<\/jats:bold>\n                      also inhibited glycoprotein VI (GPVI) downstream signaling, such as Fyn and Lyn, phospholipase C gamma 2, protein kinase C. Moreover, a surface plasmon resonance assay indicated that compound\n                      <jats:bold>6<\/jats:bold>\n                      may directly bind to GPVI, thereby interrupting the interaction of collagen and GPVI. Compound\n                      <jats:bold>6<\/jats:bold>\n                      also effectively attenuates collagen-induced granule release, calcium mobilization, and GPIIbIIIa activation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      These findings indicate that compound\n                      <jats:bold>6<\/jats:bold>\n                      can selectively inhibit GPVI, eventually suppressing platelet activation and thrombus formation while preserving hemostasis. Compound\n                      <jats:bold>6<\/jats:bold>\n                      is a GPVI antagonist and safe antiplatelet agent. Compound\n                      <jats:bold>6<\/jats:bold>\n                      also has therapeutic potential for treating cardiovascular diseases.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2025.1541255","type":"journal-article","created":{"date-parts":[[2025,6,24]],"date-time":"2025-06-24T00:10:36Z","timestamp":1750723836000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["A naphthalimide derivative exerts potent antiplatelet and antithrombotic activities without a bleeding tendency"],"prefix":"10.3389","volume":"16","author":[{"given":"Wan-Jung","family":"Lu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiun-Yi","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tzenge-Lien","family":"Shih","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ray-Jade","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ting-Yu","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei-Ting","family":"Kao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jen-Wei","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hsueh-Hsiao","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hsien-Yu","family":"Peng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kuan-Hung","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,6,24]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1601","DOI":"10.1182\/blood-2015-04-641654","article-title":"Fibrin activates GPVI in human and mouse platelets","volume":"126","author":"Alshehri","year":"2015","journal-title":"Blood"},{"key":"B2","doi-asserted-by":"publisher","first-page":"3947","DOI":"10.1021\/jm970439a","article-title":"Synthesis and biological properties of new constrained CCK-B antagonists: discrimination of two affinity states of the CCK-B receptor on transfected CHO cells","volume":"40","author":"Bellier","year":"1997","journal-title":"J. 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