Targeting PAR4 ‘an attractive antiplatelet strategy’
medwireNews: Results of a study conducted in primates suggest that a novel protease-activated receptor-4 (PAR4) antagonist could reduce thrombus formation with a lower bleeding risk than other antiplatelet agents.
As reported in Science Translational Medicine, Pancras Wong (Bristol-Myers Squibb, Pennington, New Jersey, USA) and colleagues identified the orally active, selective, reversible PAR4 antagonist BMS-986120 using a high throughput screen of 1.1 million compounds, followed by optimization.
In cynomolgus monkey models of thrombosis and bleeding, treatment with the compound resulted in a dose-dependent preservation of blood flow during thrombosis, reducing thrombus formation by 82% at a dose of 1 mg/kg compared with the vehicle control.
Treatment with the same dose of BMS-986120 also increased kidney bleeding time 2.2-fold and mesenteric bleeding time 1.8-fold compared with the vehicle control, a “limited, but statistically significant” difference.
By comparison, doses of clopidogrel resulting in 50% to 80% antithrombotic activity caused an eight- to nine-fold increase in kidney and mesenteric bleeding time, suggesting that “antagonism of the PAR4 pathway has minimal impact on hemostasis,” and could represent “a distinct advantage over existing clinical agents.”
These findings indicate that “targeting PAR4 is an attractive antiplatelet strategy,” write the researchers, noting that BMS-986120 is currently under clinical investigation.
And they conclude: “Translation of these results from nonhuman primates to the clinical setting has great potential to effectively treat large, underserved patient populations, including those with acute coronary syndromes and ischemic stroke.”
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