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
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Research Support, Non-U.S. Gov't
MeSH terms
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Blood Proteins / metabolism
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Calcium Signaling / drug effects
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Drug Discovery
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HL-60 Cells
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Humans
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Inflammation / drug therapy
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Inflammation / metabolism
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MAP Kinase Signaling System / drug effects
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Phosphorylation / drug effects
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Protein Binding
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Pyrazines / chemical synthesis*
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Pyrazines / pharmacology*
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Receptors, Formyl Peptide / agonists*
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Receptors, Lipoxin
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Structure-Activity Relationship
Substances
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Blood Proteins
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FPR1 protein, human
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FPR2 protein, human
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Pyrazines
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Receptors, Formyl Peptide
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Receptors, Lipoxin