Discovery of N-substituted-2-((arylethyl)amino)-2-(2-methoxyphenyl) acetamides: A novel family of antiplatelet agents

Abstract

The development of new antiplatelet agents is essential due to the limitations of existing therapies and the high prevalence of thrombotic disorders. As part of a project aimed at harnessing multicomponent-assisted synthetic strategies for drug discovery, we identified a novel class of potent antiplatelet compounds. Herein we report the design, synthesis, and pharmacological evaluation of a new series of N-substituted-2-((arylethyl)amino)-2-(2-methoxyphenyl)acetamides, along with structure-activity relationship analysis and a preliminary investigation of their mechanism of action. The most active compounds, 7d, 9e, and 6f, exhibited IC₅₀ values of 0.92 ± 0.24, 0.59 ± 0.10, and 0.39 ± 0.07 µM, respectively, in serotonin (30 µM) plus collagen (1 µg/mL)-induced platelet aggregation assays, outperforming sarpogrelate (IC₅₀ 5.41 ± 1.25). Functional and binding studies confirmed that these compounds act as low-affinity, weak partial agonists at 5-HT_2A, suggesting their antiplatelet effects arise from serotonin-dependent pathways rather than direct 5-HT_2A receptor antagonism. Additional experiments confirmed that the selected compounds are non-cytotoxic and significantly suppress P-selectin expression and CD63 secretion, demonstrating inhibition of both early and late stages of platelet activation. These findings introduce a new mechanistic approach to platelet inhibition, expanding the chemical space for antiplatelet drug development. Further studies should focus on molecular target identification and combination therapy potential for thrombosis treatment.

Keywords: Antiplatelet agents; Platelets; Serotonin; Site-directed modification; Ugi reaction.