Discovery of BMS-986235/LAR-1219: A Potent Formyl Peptide Receptor 2 (FPR2) Selective Agonist for the Prevention of Heart Failure

Formyl peptide receptor 2 (FPR2)
agonists can stimulate resolution
of inflammation and may have utility for treatment of diseases caused
by chronic inflammation, including heart failure. We report the discovery
of a potent and selective FPR2 agonist and its evaluation in a mouse
heart failure model. A simple linear urea with moderate agonist activity
served as the starting point for optimization. Introduction of a pyrrolidinone
core accessed a rigid conformation that produced potent FPR2 and FPR1
agonists. Optimization of lactam substituents led to the discovery
of the FPR2 selective agonist 13c, BMS-986235/LAR-1219.
In cellular assays 13c inhibited neutrophil chemotaxis
and stimulated macrophage phagocytosis, key end points to promote
resolution of inflammation. Cardiac structure and functional improvements
were observed in a mouse heart failure model following treatment with
BMS-986235/LAR-1219.