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

J Med Chem. 2019 May 23;62(10):5242-5248. doi: 10.1021/acs.jmedchem.8b01912. Epub 2019 May 13.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Blood Proteins / metabolism
  • Calcium Signaling / drug effects
  • Drug Discovery
  • HL-60 Cells
  • Humans
  • Inflammation / drug therapy
  • Inflammation / metabolism
  • MAP Kinase Signaling System / drug effects
  • Phosphorylation / drug effects
  • Protein Binding
  • Pyrazines / chemical synthesis*
  • Pyrazines / pharmacology*
  • Receptors, Formyl Peptide / agonists*
  • Receptors, Lipoxin
  • Structure-Activity Relationship

Substances

  • Blood Proteins
  • FPR1 protein, human
  • FPR2 protein, human
  • Pyrazines
  • Receptors, Formyl Peptide
  • Receptors, Lipoxin