BMS-986331

BMS-986331 is an orally active, selective N-formyl peptide receptor 2 (FPR2) agonist, showing an EC50 of 0.5 nM in humans and 1 nM in rats. It activates signaling pathways including Gαi2, GαoA, Gα12, and Gα13, recruits β-arrestin1 and β-arrestin2, and inhibits downstream cAMP. Additionally, BMS-986331 induces the expression and release of the pro-resolving cytokine IL-10. It improves cardiac structure and function in a rat model of heart failure induced by permanent coronary artery occlusion. BMS-986331 is applicable in heart failure research.

BMS-986331 (Compound 16) effectively activates human FPR2 (hFPR2) with an EC₅₀ of 0.5 nM and demonstrates a 500-fold selectivity over hFPR1. It also activates rat FPR2 with an EC₅₀ of 0.6 nM, showing 280-fold selectivity over rat FPR1. The compound exhibits high chemical stability at pH 1, with a half-life exceeding 500 minutes. When administered at 100 nM, BMS-986331 raises IL-10 levels by 211% in human whole blood. It robustly activates multiple signaling pathways via hFPR2 in HEK293 cells: Gαi2 (EC₅₀ = 0.50 nM), GαoA (EC₅₀ = 0.56 nM), Gα12/P115 (EC₅₀ = 16 nM), and Gα13/PDZ-RhoGEF (EC₅₀ = 40 nM). Additionally, BMS-986331 induces the recruitment of β-arrestin1 and β-arrestin2 to hFPR2 in HEK293 cells, with EC₅₀ values of 46 nM and 19 nM, respectively. It acts as an inhibitor of OATP1B3 with an IC₅₀ of 12 μM. Following incubation, BMS-986331 retains 88% of its initial concentration in human liver microsomes and 33% in rat liver microsomes.

BMS-986331 (Compound 16) administered orally at 10 mg/kg as a single dose can increase plasma IL-10 levels by 105% in LPS-stimulated rats. Additionally, daily oral administration of BMS-986331 (0.1-10 mg/kg/day) for six weeks maintains infarct wall thickness and improves left ventricular ejection fraction in rats with permanent coronary artery occlusion.