Design, Synthesis, Biological Evaluation, and Computational Studies of Novel Ureidopropanamides as Formyl Peptide Receptor 2 (FPR2)Agonists to Target the Resolution of Inflammation in Central Nervous System Disorders

Formyl peptide receptor 2 (FPR2) agonists can boost the resolution of inflammation and can offer alternativeapproaches for the treatment of pathologies with underlying chronic neuroinflammation, including neurodegenerative disorders.Starting from the FPR2 agonist2previously identified in our laboratory and throughfine-tuning of FPR2 potency and metabolicstability, we have identified a new series of ureidopropanamide derivatives endowed with a balanced combination of such properties.Computational studies provided insights into the key interactions of the new compounds for FPR2 activation. In mouse microglialN9 cells and in rat primary microglial cells stimulated with lipopolysaccharide, selected compounds inhibited the production of pro-inflammatory cytokines, counterbalanced the changes in mitochondrial function, and inhibited caspase-3 activity. Among the new agonists, (S)-11lstands out also for the ability to permeate the blood-brain barrier and to accumulate in the mouse brain in vivo, thus representing a valuable pharmacological tool for studies in vivo