Novel Small-Molecule Atypical Chemokine Receptor 3 (ACKR3) Agonists: Design, Synthesis, and Pharmacological Evaluation for Antiplatelet Therapy

Cardiovascular diseases are one of the leading causes of mortality worldwide. Therefore, novel therapeutic measures are urgently needed, and promising new drug targets must be explored. ACKR3, an atypical chemokine receptor, has been associated with prothrombotic events and the development of cardiovascular events. We designed, synthesized, and evaluated a series of novel small molecules ACKR3 agonists. Extensive structure-activity relationship studies resulted in several promising agonists with potencies ranging from low micromolar to nanomolar range, for example, 23 (EC50 = 111 nM, Emax = 95%) and 27 (EC50 = 69 nM, Emax = 82%) in the β-arrestin-recruitment assay. These compounds are selective for ACKR3 versus ACKR2, CXCR3, and CXCR4. Several agonists were subjected to investigations of their P-selectin expression reduction in the flow cytometry experiments. In particular, compounds 23 and 27 showed the highest potency for platelet aggregation inhibition, up to 80% and 97%, respectively. The most promising compounds, especially 27, exhibited good solubility, metabolic stability, and no cytotoxicity, suggesting a potential tool compound for the treatment of platelet-mediated thrombosis.