title: BF061, a novel antiplatelet and antithrombotic agent targeting P2Y₁₂ receptor and phosphodiesterase.
abstract: 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.
authors.affiliation: Key Laboratory of Molecular Medicine, Ministry of Education, and Department of Biochemistry and Molecular Biology, Fudan University Shanghai Medical College, Shanghai,China.
authors.forename: Liang
authors.initials: L
authors.lastname: Hu
authors.forename: Zhichao
authors.initials: Z
authors.lastname: Fan
authors.forename: Hongguang
authors.initials: H
authors.lastname: Du
authors.forename: Ran
authors.initials: R
authors.lastname: Ni
authors.forename: Si
authors.initials: S
authors.lastname: Zhang
authors.forename: Kanhua
authors.initials: K
authors.lastname: Yin
authors.forename: Jianqin
authors.initials: J
authors.lastname: Ye
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Xunbin
authors.initials: X
authors.lastname: Wei
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Zhang
authors.forename: Peter L
authors.initials: PL
authors.lastname: Gross
authors.forename: Satya P
authors.initials: SP
authors.lastname: Kunapuli
authors.forename: Zhongren
authors.initials: Z
authors.lastname: Ding
mesh_terms: D000241:Adenosine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D000249:Adenosine Monophosphate / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D000818:Animals; D004195:Disease Models, Animal; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000009:adverse effects; D005343:Fibrinolytic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D015539:Platelet Activation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D058921:Purinergic P2Y Receptor Antagonists / Q000008:administration & dosage* / Q000009:adverse effects; D013927:Thrombosis / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology
chemical_list: C571404:2-ethylthio-6-phenethylaminoadenosine; D004791:Enzyme Inhibitors; D005343:Fibrinolytic Agents; D010975:Platelet Aggregation Inhibitors; D058921:Purinergic P2Y Receptor Antagonists; D000249:Adenosine Monophosphate; C117446:cangrelor; D010727:Phosphoric Diester Hydrolases; D000241:Adenosine