Substituted Pyridazin-3(2H)-ones as Highly Potent and Biased Formyl Peptide Receptor Agonists

Herein we describe the development of a focused series of functionalized pyridazin-3(2H)-one-based formyl peptide receptor (FPR) agonists that demonstrate high potency and biased agonism. The compounds described demonstrated biased activation of prosurvival signaling, ERK1/2 phosphorylation, through diminution of the detrimental FPR1/2-mediated intracellular calcium (Ca-i(2+)) mobilization. Compound 50 showed an EC50 of 0.083 mu M for phosphorylation of ERK1/2 and an approximate 20-fold bias away from Ca-i(2+) mobilization at the hFPR1.