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Bioorg Med Chem Lett. 2016 Jun 15;26(12):2739-2754. doi: 10.1016/j.bmcl.2016.04.030. Epub 2016 Apr 13.

State of affairs: Design and structure-activity relationships of reversible P2Y12 receptor antagonists.

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Galecto Biotech, Sahlgrenska Science Park, Medicinaregatan 8A, S-413 46 Gothenburg, Sweden. Electronic address:
Integrative Research Laboratories, Arvid Wallgrens Backe 20, S-413 46 Gothenburg, Sweden.


Myocardial infarction and stroke are the most common causes of mortality and morbidity in the developed world. Therefore the search for antiplatelet therapy has been in focus for the last decades, in particular the search for new P2Y12R antagonists. The first P2Y12R drug developed, clopidogrel, is a major success but there is still room for improvement with respect to bleeding profile and non-responders. These liabilities could be due to the fact that clopidogrel is a pro-drug and upon activation binds covalently to the receptor. Therefore a lot of effort has gone into identifying reversible inhibitors. One recent example is ticagrelor, which in clinical studies have been shown to be safer and even reduce rate of death from vascular events as compared head to head with clopidogrel. We here review the medicinal chemistry strategies used in the design of new reversible P2Y12R antagonists. In addition, we also present structure based design studies based on the recently published agonist and antagonist X-ray structures of P2Y12R.


Acute coronary syndrome (ACS); Antithrombotics; G protein-coupled receptors; P2Y(12) receptor; Platelet aggregation; Thromboembolism

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