Design, Synthesis, and Biological Evaluation of Novel Heteroaryl, Squaramide, and Indolcarboxamide Derivatives as Formyl Peptide Receptor 2 Agonists to Target Neuroinflammation

Recent research reveals Formyl Peptide Receptor 2 (FPR2) as a relevant G Protein-Coupled Receptor involved in the resolution phase of inflammation. Therefore, FPR2 agonists are promising agents to tackle neuroinflammatory-based diseases, such as Alzheimer's Disease or Autism Spectrum Disorder. Here, we describe the synthesis and biological evaluation of novel FPR2 agonists designed through the bioisosteric replacement of the phenyl urea function in the potent FPR2 agonist (S)-1-(3-(4-cyanophenyl)-1-(indolin-1-yl)-1-oxopropan-2-yl)-3-(4-fluorophenyl)urea (5), obtaining novel heteroaryl, squaramide, and indolcarboxamide derivatives. The structural modification had a profound effect on FPR2 agonist potency, metabolic stability, aqueous solubility, and cell permeability, resulting in compounds with distinct profiles. Computational studies have shown that the new compounds exhibit the same contacts with key Amino acids in the binding site as the starting FPR2 agonist 5. However, subtle differences in the orientation or the presence and position of heteroatoms in the selected scaffolds translate to substantial differences in FPR2 potency. Among the new compounds, (S)-9a, (S)-12a, and (S)-16b demonstrated neuroprotective, anti-inflammatory, and pro-resolving properties in mouse primary microglial cells, stimulated with lipopolysaccharide. Although the replacement of the phenyl urea with different scaffolds did not lead to the identification of a bioisostere, compounds (S)-9a, (S)-12a, and (S)-16b represent a starting point for the development of a new class of FPR2 agonists.

aqueous solubility; bioisosteres; formyl peptide receptor 2; metabolic stability; microglia; neuroinflammation; structure–activity relationships.