Inhibitory effects of J78, a newly synthesized 1,4-naphthoquinone derivative, on experimental thrombosis and platelet aggregation.
Several compounds with the backbone of 1,4-naphthoquinone chemical structure have been reported to display antiplatelet and antithrombotic activities, indicating that this congener compound may be a new source in the antithrombotic drug development. In the present study, the possible antiplatelet activity and antithrombotic efficacy of J78 (2-chloro-3-[2'-bromo, 4'-fluoro- phenyl]-amino-8-hydroxy-1,4-naphthoquinone), a newly synthesized 1,4-naphthoquinone derivative, were examined. Orally administered J78 (50, 100 mg/kg) dose dependently protected mice against the collagen + epinephrine-induced thromboembolic death. Orally administered J78 also significantly inhibited the ADP- and collagen-induced rat platelet aggregation ex vivo, with inhibition values of 44 and 40%, respectively. J78 inhibited the collagen-, arachidonic acid- and thrombin-induced human platelet aggregation concentration dependently in vitro, with IC(50) values of 7.8 +/- 0.4, 10.1 +/- 0.4 and 18.4 +/- 2.0 micromol/l, respectively. It was also active in inhibiting Ca(2+) ionophore, A23187-induced platelet aggregation, suggesting that J78 may have an inhibitory effect on Ca(2+) mobilization. J78, however, did not alter coagulation parameters such as activated partial thromboplastin time and prothrombin time in human plasma. Taken together, these results suggest that J78 may be a promising antithrombotic agent, and its antithrombotic activity may be due to antiplatelet rather than anticoagulation activity.
College of Pharmacy, Chungbuk National University, Cheongju, Korea.
Yong-Ri
YR
Jin
Chung-Kyu
CK
Ryu
Chang-Kiu
CK
Moon
Mi-Ra
MR
Cho
Yeo-Pyo
YP
Yun
D000244:Adenosine Diphosphate / Q000494:pharmacology; D000818:Animals; D003094:Collagen; D004837:Epinephrine; D005343:Fibrinolytic Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D006801:Humans; D066298:In Vitro Techniques; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008297:Male; D051379:Mice; D009285:Naphthoquinones / Q000494:pharmacology* / Q000627:therapeutic use*; D010314:Partial Thromboplastin Time; D010974:Platelet Aggregation / Q000187:drug effects*; D011655:Pulmonary Embolism / Q000097:blood / Q000139:chemically induced / Q000188:drug therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014662:Vasoconstrictor Agents
C487700:2-chloro-3-(2'-bromo-4'-fluorophenyl)amino-8-hydroxy-1,4-naphthoquinone; D005343:Fibrinolytic Agents; D009285:Naphthoquinones; D014662:Vasoconstrictor Agents; D000244:Adenosine Diphosphate; D003094:Collagen; D007770:L-Lactate Dehydrogenase; D004837:Epinephrine