Formyl peptide receptors (FPRs), which belong to the G-protein coupled receptor (GPCR) family, play important roles in host defense and inflammation. In humans, three subtypes (FPR1, 2, 3) have been identified. FPR1 causes pro-inflammatory responses when activated with ligands such as <i>N</i>-formyl-methionyl-leucyl-phenylalanine produced from bacteria. In contrast, FPR2 has been reported to resolve inflammation when activated by ligands such as Annexin A1. Although FPR2 is a promising target for treatment of various inflammatory diseases, there are no compounds launched as therapeutic agents to date. In this context, we focused on the discovery of small molecule FPR2 agonists with selectivity over FPR1. A series of four to six membered lactam urea derivatives were synthesized that produced potent human FPR1 and 2 agonists. Further optimization of the pyrrolidinone scaffold led to selective FPR2 agonists with picomolar in vitro activity. Among the derivatives evaluated, highly potent and selective agonist, BMS-986235/LAR-1219, was identified as a promising clinical candidate.

Discovery of clinical candidate, BMS-986235/LAR-1219: Design and optimization of selective 4-phenylpyrrolidinone FPR2 agonists

2019 Fall National Meeting

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