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Quantifying Agonist Activity at G Protein-coupled Receptors
Published on: December 26, 2011
Substituted Pyridazin-3(2 H)-ones as Highly Potent and Biased Formyl Peptide Receptor Agonists
Girdhar Singh Deora1, Cheng Xue Qin2,3, Elizabeth A Vecchio2
1Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences , Monash University , Parkville , Victoria 3052 , Australia.
Abstract:
Herein we describe the development of a focused series of functionalized pyridazin-3(2 H)-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 (Cai2+) mobilization. Compound 50 showed an EC50 of 0.083 μM for phosphorylation of ERK1/2 and an approximate 20-fold bias away from Cai2+ mobilization at the hFPR1.
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