Tackling neuroinflammation with H2S releasing FPR2 agonists

Neuroinflammation is a hallmark of neurodegenerative diseases. It has been linked to tissue damage by oxidative stress, driving neurodegeneration, and its resolution could alter disease progression and outcome [1]. Formyl Peptide Receptor 2 (FPR2) is a G protein-coupled receptor (GPCR), highly expressed by microglial cells and binding several different ligands which elicit either pro-inflammatory or anti-inflammatory effects depending on their structure. This makes it a notable target for the resolution of neuroinflammation [2]. In the past, our group developed the ureidopropanamide class of FPR2 agonists. More recent efforts have led us to try and enhance the anti-inflammatory capabilities of these compounds following different strategy. Herein we present the introduction of H2S releasing moieties into the ureidopropanamide scaffold. H2S is a gaseous neuromodulator and neuroprotector, active as a calcium influx regulator and as an anti-inflammatory and antioxidant agent [3]. Thus we converted the ureido and amide moieties of our compounds into the corresponding thioureas and thioamides. Figure 1: scaffolds of ureidopropanamide FPR2 agonists and their thioureido and thioamide counterparts. We assayed the activity of our compounds as FPR2 agonists, their capacity as H2S releasers and their neuroprotective activity in models of neuroinflammation, showing their potential as new anti-inflammatory drugs. [1] Teleanu, D.M. et al. Int J Mol Sci (2022), 23, 5938 [2] Mastromarino, M. et al. J Med Chem (2022), 65, 5004–5028 [3] Dilek, N. et al. Pharmacol Res (2020), 161, 105119