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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   *
1   Key Laboratory of Molecular Medicine, Ministry of Education, and Department of Biochemistry and Molecular Biology, Fudan University Shanghai Medical College, Shanghai, China
,
Zhichao Fan   *
2   Department of Chemistry, and Institutes of Biomedical Sciences, Fudan University, Shanghai, China
,
Hongguang Du
3   College of Science, Beijing University of Chemical Technology, Beijing, China
,
Ran Ni
4   Thrombosis and Atherosclerosis Research Institute, McMaster University, Hamilton, Ontario, Canada
,
Si Zhang
1   Key Laboratory of Molecular Medicine, Ministry of Education, and Department of Biochemistry and Molecular Biology, Fudan University Shanghai Medical College, Shanghai, China
,
Kanhua Yin
1   Key Laboratory of Molecular Medicine, Ministry of Education, and Department of Biochemistry and Molecular Biology, Fudan University Shanghai Medical College, Shanghai, China
,
Jianqin Ye
1   Key Laboratory of Molecular Medicine, Ministry of Education, and Department of Biochemistry and Molecular Biology, Fudan University Shanghai Medical College, Shanghai, China
,
Yan Zhang
1   Key Laboratory of Molecular Medicine, Ministry of Education, and Department of Biochemistry and Molecular Biology, Fudan University Shanghai Medical College, Shanghai, China
,
Xunbin Wei
2   Department of Chemistry, and Institutes of Biomedical Sciences, Fudan University, Shanghai, China
,
Xiaohui Zhang
5   Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
,
Peter L. Gross
4   Thrombosis and Atherosclerosis Research Institute, McMaster University, Hamilton, Ontario, Canada
,
Satya P. Kunapuli
5   Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
,
Zhongren Ding
1   Key Laboratory of Molecular Medicine, Ministry of Education, and Department of Biochemistry and Molecular Biology, Fudan University Shanghai Medical College, Shanghai, China
› Author Affiliations Financial support: This work was supported in part by National Natural Science Foundation of China [No.30772564, 30973529], National Drug Innovative Program from Ministry of Science and Technology of China [2009ZX09301–011], Program for Professor of Special Appointment (Eastern Scholar) at Shanghai Institutions of Higher Learning to ZD, and a grant from National Institutes of Health National Heart, Lung and Blood Institute [grant HL60683] to SPK. KY is a recipient of Hui-Chun Chin and Tsung-Dao Lee Chinese Undergraduate Research Endowment (CURE).
Further Information

Publication History

Received: 13 June 2011

Accepted after major revision: 31 August 2011

Publication Date:
27 November 2017 (online)

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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

* These authors contributed equally to this work.


 

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