From Lead to Clinical Candidate: Discovery of BMS-986331 as a Potent and Selective <i>N</i> -Formyl Peptide Receptor 2 Agonist

FPR2 belongs to a subfamily of GPCRs that play a vital role in host defense and regulation of inflammation. FPR2 modulation is proposed to enhance myocardial wound healing postmyocardial infarction, diminish adverse myocardial remodeling, and alter progression to heart failure. Herein, we report lead optimization efforts originating from our previously reported lead compound <b>1</b>, delivering compound <b>16</b> (<b>BMS-986331</b>), which advanced into clinical trials. Compound <b>16</b> is a highly potent and selective FPR2 agonist that induces the expression and release of the pro-resolution cytokine IL-10 in both human whole blood and in acute rat models of inflammation. Moreover, chronic treatment with <b>16</b> improves cardiac structure and function in a rat heart failure model after permanent coronary artery occlusion. The physicochemical and ADMET properties of <b>16</b> combined with high potency lead to a predicted low oral dose in humans.