BF0801, a novel adenine derivative, inhibits platelet activation via phosphodiesterase inhibition and P2Y12 antagonism

Si Zhang; Liang Hu; Hongguang Du; Yan Guo; Yan Zhang; Haixia Niu; Jianguo Jin; Jian Zhang; Junling Liu; Xiaohui Zhang; Satya P. Kunapuli; Zhongren Ding

doi:10.1160/TH10-05-0285

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2010; 104(04): 845-857
DOI: 10.1160/TH10-05-0285

New Technologies, Diagnostic Tools and DRugs

Schattauer GmbH

BF0801, a novel adenine derivative, inhibits platelet activation via phosphodiesterase inhibition and P2Y₁₂ antagonism

Authors

Si Zhang

¹Key Laboratory of Molecular Medicine, Ministry of Education, and Department of Biochemistry and Molecular Biology, Fudan University Shanghai Medical College, Shanghai, China
Liang Hu

¹Key Laboratory of Molecular Medicine, Ministry of Education, and Department of Biochemistry and Molecular Biology, Fudan University Shanghai Medical College, Shanghai, China
Hongguang Du

²College of science, Beijing University of Chemical Technology, Beijing, China
Yan Guo

³Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
Yan Zhang

¹Key Laboratory of Molecular Medicine, Ministry of Education, and Department of Biochemistry and Molecular Biology, Fudan University Shanghai Medical College, Shanghai, China
Haixia Niu

⁴Institutes of Medical Sciences, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
Jianguo Jin

⁵Department of Physiology, Temple University School of Medicine, Philadelphia, Pennsylvania, USA
Jian Zhang

⁴Institutes of Medical Sciences, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
Junling Liu

⁴Institutes of Medical Sciences, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
Xiaohui Zhang

³Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
Satya P. Kunapuli

⁵Department of Physiology, Temple University School of Medicine, Philadelphia, Pennsylvania, USA
Zhongren Ding

¹Key Laboratory of Molecular Medicine, Ministry of Education, and Department of Biochemistry and Molecular Biology, Fudan University Shanghai Medical College, Shanghai, China

Abstract

Summary

Though antiplatelet drugs are proven beneficial to patients with coronary heart disease and stroke, more effective and safer antiplatelet drugs are still needed. In this study we report the antiplatelet effects and mechanism of BF0801, a novel adenine derivative. BF0801 dramatically inhibited platelet aggregation and ATP release induced by ADP, 2MeSADP, AYPGKF, SFLLRN or convulxin without affecting shape change in vitro. It also potentiated the inhibitory effects of adenosine-based P2Y₁₂ antagonist AR-C69931MX or phosphodiesterase (PDE) inhibitor IBMX on platelet aggregation. The cAMP levels in both resting and forskolin-stimulated platelets were increased by BF0801 suggesting its PDE inhibitor activity, which is further confirmed by the concentration-dependent suppression of BF0801 on the native and recombinant PDE. Similar to AR-C69931MX, BF0801 drastically inhibited 2MeSADP-induced adenylyl cyclase inhibition in platelets indicating its P2Y₁₂ antagonism activity, which is substantiated by the inhibition of BF0801 on the interaction between ADP and P2Y₁₂ receptor expressed in CHO-K1 cells measured by atomic force microscopy. Moreover, we confirmed the antiplatelet effects of BF0801 using platelets from rats intravenously given BF0801. In summary, for the first time we developed a novel adenine derivative bearing dual activities of PDE inhibition and P2Y₁₂ antagonism, which may have therapeutic advantage as a potential antithrombotic drug.

Keywords

Antiplatelet - adenine derivative - cAMP - P2Y₁₂ - phosphodiesterase

Full Text

References

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