Research ArticleCOAGULATION

Blockade of protease-activated receptor-4 (PAR4) provides robust antithrombotic activity with low bleeding

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Science Translational Medicine  04 Jan 2017:
Vol. 9, Issue 371, eaaf5294
DOI: 10.1126/scitranslmed.aaf5294

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This antiplatelet agent is just right

Antiplatelet agents are common drugs that are used to prevent thrombotic events such as stroke in patients at high risk. Unfortunately, a frequent side effect of these drugs is excessive bleeding because they indiscriminately suppress thrombotic function. To improve on the safety margin of antiplatelet agents, Wong et al. identified a new target for treatment, a platelet receptor called PAR4. The authors developed a small-molecule drug against this target and evaluated its efficacy and safety in animal models. In head-to-head comparisons, the new drug was no less effective than clopidogrel, an antiplatelet agent widely used in the clinic, but it had a much larger therapeutic window.

Abstract

Antiplatelet agents are proven efficacious treatments for cardiovascular and cerebrovascular diseases. However, the existing drugs are compromised by unwanted and sometimes life-threatening bleeding that limits drug usage or dosage. There is a substantial unmet medical need for an antiplatelet drug with strong efficacy and low bleeding risk. Thrombin is a potent platelet agonist that directly induces platelet activation via the G protein (heterotrimeric guanine nucleotide–binding protein)–coupled protease-activated receptors PAR1 and PAR4. A PAR1 antagonist is approved for clinical use, but its use is limited by a substantial bleeding risk. Conversely, the potential of PAR4 as an antiplatelet target has not been well characterized. Using anti-PAR4 antibodies, we demonstrated a low bleeding risk and an effective antithrombotic profile with PAR4 inhibition in guinea pigs. Subsequently, high-throughput screening and an extensive medicinal chemistry effort resulted in the discovery of BMS-986120, an orally active, selective, and reversible PAR4 antagonist. In a cynomolgus monkey arterial thrombosis model, BMS-986120 demonstrated potent and highly efficacious antithrombotic activity. BMS-986120 also exhibited a low bleeding liability and a markedly wider therapeutic window compared to the standard antiplatelet agent clopidogrel tested in the same nonhuman primate model. These preclinical findings define the biological role of PAR4 in mediating platelet aggregation. In addition, they indicate that targeting PAR4 is an attractive antiplatelet strategy with the potential to treat patients at a high risk of atherothrombosis with superior safety compared with the current standard of care.

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