Human platelets possess 3 purinergic receptors (P2Y12, P2Y1, and P2X1), which collectively orchestrate key steps leading to platelet activation and aggregation (Figure). Until now, the selective blockade of the platelet P2Y12 ADP receptor, combined with the inhibition of thromboxane production by aspirin, has remained the backbone of pharmacotherapy for patients presenting with acute coronary syndrome or undergoing percutaneous coronary intervention.1 Figure. The investigational modified diadenosine tetraphosphate (Ap4A) derivative, GLS-409, in the context of major classes of currently approved antiplatelet therapies and their respective pharmacologic targets. COX indicates cyclooxygenase; F, fibrinogen; GP, glycoprotein; PAR, protease-activated receptor; and T, thrombin. See accompanying article on page 501 Despite significant progress in the attenuation of excess platelet activity in these high-risk settings, percutaneous coronary intervention–related thrombotic complications, including stent thrombosis, and severe bleeding continue to be major sources of morbidity and mortality. Early after acute coronary syndrome, patients may …

2016-03-01·Arteriosclerosis, Thrombosis, and Vascular Biology1区 · 医学

Synergistic Inhibition of Both P2Y ₁ and P2Y ₁₂ Adenosine Diphosphate Receptors As Novel Approach to Rapidly Attenuate Platelet-Mediated Thrombosis

1区 · 医学

Article

作者: Gremmel, Thomas ; Przyklenk, Karin ; Michelson, Alan D ; Frelinger, Andrew L ; Wider, Joseph ; Yanachkov, Ivan B ; Yanachkova, Milka I ; Wright, George E ; Undyala, Vishnu V R

Objective— Unlike currently approved adenosine diphosphate receptor antagonists, the new diadenosine tetraphosphate derivative GLS-409 targets not only P2Y 12 but also the second human platelet adenosine diphosphate receptor P2Y 1 and may, therefore, be a promising antiplatelet drug candidate. The current study is the first to investigate the in vivo antithrombotic effects of GLS-409. Approach and Results— We studied (1) the in vivo effects of GLS-409 on agonist-stimulated platelet aggregation in anesthetized rats, (2) the antithrombotic activity of GLS-409 and the associated effect on the bleeding time in a canine model of platelet-mediated coronary artery thrombosis, and (3) the inhibition of agonist-stimulated platelet aggregation by GLS-409 versus selective P2Y 1 and P2Y 12 inhibition in vitro in samples from healthy human subjects before and 2 hours after aspirin intake. In vivo treatment with GLS-409 significantly inhibited adenosine diphosphate- and collagen-stimulated platelet aggregation in rats. Further, GLS-409 attenuated cyclic flow variation, that is, platelet-mediated thrombosis, in vivo in our canine model of unstable angina. The improvement in coronary patency was accompanied by a nonsignificant 30% increase in bleeding time. Of note, GLS-409 exerted its effects without affecting rat and canine hemodynamics. Finally, in vitro treatment with GLS-409 showed effects similar to that of cangrelor and the combination of cangrelor with the selective P2Y 1 inhibitor MRS 2179 on agonist-stimulated platelet aggregation in human platelet-rich plasma and whole blood before and 2 hours after aspirin intake. Conclusions— Synergistic inhibition of both P2Y 1 and P2Y 12 adenosine diphosphate receptors by GLS-409 immediately attenuates platelet-mediated thrombosis and effectively blocks agonist-stimulated platelet aggregation irrespective of concomitant aspirin therapy.

Scientific Reports

Publisher Correction: GLS-409, an Antagonist of Both P2Y1 and P2Y12, Potently Inhibits Canine Coronary Artery Thrombosis and Reversibly Inhibits Human Platelet Activation

作者: Yanachkova, Milka I ; Yanachkov, Ivan B ; Frelinger, Andrew L ; Wright, George E ; Przyklenk, Karin ; Michelson, Alan D ; Smolensky Koganov, Elena

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.

100 项与 GLS-409 (GLSynthesis) 相关的药物交易

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