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, throug...

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Published inJournal of medicinal chemistry Vol. 62; no. 10; pp. 5242 - 5248
Main Authors Deora, Girdhar Singh, Qin, Cheng Xue, Vecchio, Elizabeth A, Debono, Aaron J, Priebbenow, Daniel L, Brady, Ryan M, Beveridge, Julia, Teguh, Silvia C, Deo, Minh, May, Lauren T, Krippner, Guy, Ritchie, Rebecca H, Baell, Jonathan B
Format Journal Article
LanguageEnglish
Published WASHINGTON American Chemical Society 23.05.2019
Amer Chemical Soc
Subjects
Chemistry, Medicinal
Life Sciences & Biomedicine
Pharmacology & Pharmacy
Science & Technology
TARGET
FUNCTIONAL SELECTIVITY
REPERFUSION INJURY
RESOLUTION
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Summary: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 (Cai 2+) mobilization. Compound 50 showed an EC50 of 0.083 μM for phosphorylation of ERK1/2 and an approximate 20-fold bias away from Cai 2+ mobilization at the hFPR1.
Bibliography:ObjectType-Article-1
SourceType-Scholarly Journals-1
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content type line 23
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.8b01912