Exploring the antiplatelet activity of serotonin 5-HT2A receptor antagonists bearing 6-fluorobenzo[d]isoxazol-3-yl)propyl) motif– as potential therapeutic agents in the prevention of cardiovascular diseases

• Published in: Biomedicine & pharmacotherapy 2022-01, Vol.145, p.112424-112424, Article 112424
• Main Authors: Marcinkowska, Monika, Kubacka, Monika, Zagorska, Agnieszka, Jaromin, Anna, Fajkis-Zajaczkowska, Nikola, Kolaczkowski, Marcin
• Format: Article
• Language: English
• Subjects: 5-HT2A receptor antagonist; 6-fluorobenzo[d]isoxazole derivatives; Antiplatelet agents; Cardiovascular research; Ketanserin; Sarpogrelate
• ISSN: 0753-3322; 1950-6007
• DOI: 10.1016/j.biopha.2021.112424

Small drug-like molecules that can block the function of serotonin 5-HT2A receptors have garnered considerable attention due to their ability to inhibit platelet aggregation and the possible prevention of atherosclerotic lesions. Although clinical data provided compelling evidence for the efficacy of this approach in the prevention of various cardiovascular conditions, the chemical space of 5-HT2A receptor antagonists is limited to ketanserin and sarpogrelate. To expand the portfolio of novel chemical motifs with potential antiplatelet activity, we evaluated the antiplatelet activity of a series of 6-fluorobenzo[d]isoxazole derivatives that possess a high affinity for 5-HT2A receptor. Here we describe in vitro studies showing that 6-fluorobenzo[d]isoxazole derivatives exert promising antiplatelet activity in three various in vitro models of platelet aggregation, as well as limit serotonin-induced vasoconstriction. Compound AZ928 showed in vitro activity greater than the clinically approved drug sarpogrelate. In addition to promising antiplatelet activity, the novel series was characterized by a favorable safety profile. Our findings show that the novel series exerts promising antiplatelet efficacy while being deprived of potential side effects, such as hemolytic activity, which render these compounds as potential substances for further investigation in the field of cardiovascular research. [Display omitted] •The 6-fluorobenzo[d]isoxazole series shows a high affinity for the 5-HT2A receptor.•Derivatives of 6-fluorobenzo[d]isoxazole exert antiplatelet activity.•Antiplatelet agents acting via 5-HT2AR hold promise in cardiovascular research.