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

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

› Author Affiliations

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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