bf066, a novel dual target antiplatelet agent without significant bleedingbf066,一种新颖的双目标抗血小板剂没有显著的出血.pdfVIP

BF066, a Novel Dual Target Antiplatelet Agent without Significant Bleeding 1,2. 2,3 . 4 2 4 4 5 ChangE Pan , Xunbin Wei * , Jianqin Ye , Guangda Liu , Si Zhang , Yan Zhang , Hongguang Du , Zhongren Ding4* 1 School of Life Science, Fudan University, Shanghai, China, 2 Institutes of Biomedical Sciences, Fudan University, Shanghai, China, 3 Med-X Research Institute and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China, 4 Key Laboratory of Molecular Medicine, Ministry of Education, and Department of Biochemistry and Molecular Biology, Fudan University Shanghai Medical College, Shanghai, China, 5 College of Science, Beijing University of Chemical Technology, Chaoyang District, Beijing, China Abstract In this study, we report BF066, a novel adenine derivative, inhibits platelet activation and thrombosis via the adenosine receptor (A2A) activation and phosphodiesterase (PDE) inhibition. BF066 inhibits platelet aggregation and ATP releasing induced by multiple platelet agonists in a dose-dependent manner. The inhibition of BF066 on ADP-induced aggregation is potentiated by adenosine and can be dramatically antagonized by the A2A antagonist SCH58261. BF066 also inhibits the PDE activity and platelet spreading on fibrinogen. In FeCl3-injured mouse mesenteric arterial thrombosis model, BF066 prevents thrombus formation effectively, similar to clopidogrel. Intriguingly, at dose achieving similar antithrombotic effect compared to clopidogrel, BF066 does not increase bleeding significantly. Taken together, these results suggest that BF066 may be an effective and safe antiplatelet agent targeting both PDE and A2A. Considering the successful use of combined