Abstract Nine synthetic isoxazoles were evaluated as antiplatelet agents and studied the possible mechanism of more active compound. The initial screening was evaluating all compounds against platelet aggregation assays. The most active compound was isoxazole 8 showing an inhibition of platelet aggregation around 70%. In subsequent experiments, ADP and collagen were used as agonists to explore the possible inhibitory mechanisms of isoxazole 8 in platelet aggregation and secretion. We reported the effect of isoxazole 8 for reducing the expression of inflammatory markers, such as soluble CD40 ligand (sCD40L) and soluble P-selectin (sP-selectin), on activated platelets. Of this form, an inhibition of sCD40L and sP-selectin can prevent the onset of an atherosclerotic lesion.