Polyfluorinated 3-phenyl-2-isoxazoline-5-carboxamides as inhibitors of platelet aggregation

The study of novel platelet aggregation inhibitors is important for the development of more effective and selective antithrombotic agents. In this study, we compared the inhibitory activity of compounds—derivatives of 3-phenyl-2-isoxazoline-5-carboxamide containing three to five fluorine atoms in the aromatic substituent (10 new compounds)—and the reference drug clopidogrel against adenosine diphosphate (ADP)- and collagen-induced platelet aggregation. For each compound, the percentage of platelet aggregation inhibition was measured over a concentration range of 1–25 mM upon activation with ADP and collagen using light transmission aggregometry. All newly obtained compounds demonstrated a dose-dependent effect but were less effective when compared with clopidogrel. Compound 5 exhibited consistently high non-selective activity (62% and 63.5%). Compounds with selective action were identified: compounds 3, 8, and 10 were more effective at inhibiting ADP-dependent aggregation (difference of 20%–30%), whereas compounds 4, 6, 7, and 9 were more effective against collagen-induced aggregation (difference of up to 28%). The obtained data indicate the existence of compounds with a selective action profile against different platelet activation pathways despite having nearly identical structures. The most promising compounds for further research are compound 5 (broad spectrum), compound 7 (collagen-selective), and compound 10 (ADP-selective).