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Thromb Res. 2018 Oct;170:192-199. doi: 10.1016/j.thromres.2018.08.022. Epub 2018 Sep 1.

Study on antiplatelet effect of a new thiophenopyridine platelets P2Y12 receptor antagonist DV-127.

Author information

1
Department of Pharmacology, School of Pharmacy, Jilin University, Fujin Road, Changchun 130021, Jilin, China.
2
College of Life Sciences, Jilin University, Qianjin Street, Changchun 130012, Jilin, China. Electronic address: gujk@jlu.edu.cn.
3
College of Life Sciences, Jilin University, Qianjin Street, Changchun 130012, Jilin, China; Tasly Academy, Tasly Holding Group Co.,Ltd., Tianjin 300410, China.
4
Department of Pharmacology, School of Pharmacy, Jilin University, Fujin Road, Changchun 130021, Jilin, China. Electronic address: caoxia@jlu.edu.cn.

Abstract

P2Y12 receptor antagonists are a class of drugs that act on platelet P2Y12 receptors and inhibit adenosine diphosphate-induced platelet aggregation. As a thienopyridine antiplatelet agent which is approved by the US Food and Drug Administration for the treatment of cardiovascular diseases, currently, clopidogrel was once considered to be the most safe and effective antiplatelet drug in the P2Y12 receptor antagonists, however, it has become increasingly clear that clopidogrel does not satisfactorily inhibit the platelets of approximately one-third of patients. This is in part due to clopidogrel is a prodrug and reliance on multiple cytochrome P450 enzymes for conversion into its active metabolite. Prasugrel and ticagrelor reduces the risk of adverse cardiovascular events compared to clopidogrel in acute coronary syndromes patients, however, the cardiovascular benefit of both drugs is counter-balanced by increased rates of spontaneous bleeding. Unlike clopidogrel, which is a prodrug, cangrelor is an active drug not requiring metabolic conversion, despite fewer bleeding events during cardiac surgery, cangrelor carries the risk of potential autoimmune reactions manifesting as breathlessness. DV-127 was synthesized by using three generations of thienopyridine P2Y12 receptor antagonists as research models, using high resolution mass spectrometry, selective deuteration, and 2,7-position replacement groups technologies in order to maximize cardiovascular benefit while minimizing adverse effects on hemostasis. Our results show that although the dose of DV-127 is greatly reduced, it can achieve similar anticoagulant and antiplatelet effects as clopidogrel, and DV-127 can more strongly inhibit the release of α-granules even though the inhibitory effect of dense granules is similar to clopidogrel.

KEYWORDS:

Clopidogrel; DV-127; Dense granules; Platelet; Selective deuteration; α-Granules

PMID:
30199785
DOI:
10.1016/j.thromres.2018.08.022
[Indexed for MEDLINE]

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