BF061, a novel antiplatelet and antithrombotic agent targeting P2Y12 receptor and phosphodiesterase

Liang Hu; Zhichao Fan; Hongguang Du; Ran Ni; Si Zhang; Kanhua Yin; Jianqin Ye; Yan Zhang; Xunbin Wei; Xiaohui Zhang; Peter L. Gross; Satya P. Kunapuli; Zhongren Ding

doi:10.1160/TH11-06-0400

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2011; 106(06): 1203-1214
DOI: 10.1160/TH11-06-0400

New Technologies, Diagnostic Tools and Drugs

Schattauer GmbH

BF061, a novel antiplatelet and antithrombotic agent targeting P2Y₁₂ receptor and phosphodiesterase

Authors

Liang Hu^*

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

²Department of Chemistry, and Institutes of Biomedical Sciences, Fudan University, Shanghai, China
Hongguang Du

³College of Science, Beijing University of Chemical Technology, Beijing, China
Ran Ni

⁴Thrombosis and Atherosclerosis Research Institute, McMaster University, Hamilton, Ontario, Canada
Si Zhang

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

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

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

²Department of Chemistry, and Institutes of Biomedical Sciences, Fudan University, Shanghai, China
Xiaohui Zhang

⁵Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
Peter L. Gross

⁴Thrombosis and Atherosclerosis Research Institute, McMaster University, Hamilton, Ontario, Canada
Satya P. Kunapuli

⁵Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
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

The addition of phosphodiesterase (PDE) inhibitors has been reported to potentiate the antithrombotic effects of P2Y₁₂ antagonists without increasing bleeding risk. In this study, we report that a potent antiplatelet agent, 2-ethylthio-6-phenethylaminoadenosine (BF061), inhibits platelet activation and thrombosis via P2Y₁₂ antagonism and PDE inhibition. We explored the antiplatelet mechanism of BF061 by measuring cAMP, cGMP levels, PDE activity, and the interaction between ADP and P2Y₁₂ using atomic force microscopy. The antithrombotic effect of BF061 was evaluated in mice using intravital microscopy in FeCl₃-induced mesenteric and laser-induced cremasteric arterial thrombosis models. BF061 robustly inhibited platelet aggregation and ATP release induced by multiple platelet agonists via P2Y₁₂ antagonism and PDE inhibition. Interestingly, despite being structurally similar to BF061, P2Y₁₂ receptor antagonist AR-C69931MX had no effect on human platelet PDE. In FeCl3-induced mesenteric arterial thrombosis model, BF061 effectively prevented thrombus formation similarly to clopidogrel; it also reduced thrombus volume in laser-injured cremaster arteriole model. In contrast, BF061 induced dramatically less bleeding at an antithrombotic dose compared to clopidogrel. In summary, we developed a novel antiplatelet and antithrombotic agent targeting both P2Y₁₂ and PDE. Given the prevalence of combined antiplatelet therapy in clinical practice, an antiplatelet agent bearing dual activities may have therapeutic advantage as a potential antithrombotic drug.

Keywords

Antiplatelet - antithrombotic - BF061 - PDE inhibitor - P2Y₁₂ receptor antagonist

Full Text

References

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