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

Girdhar Singh Deora, Cheng Xue Qin, Elizabeth A. Vecchio, Aaron J. Debono, Daniel L. Priebbenow, Ryan M. Brady, Julia Beveridge, Silvia C. Teguh, Minh Deo, Lauren T. May, Guy Krippner, Rebecca H. Ritchie, Jonathan B. Baell

Research output: Contribution to journalArticleResearchpeer-review

Abstract

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 EC 50 of 0.083 μM for phosphorylation of ERK1/2 and an approximate 20-fold bias away from Ca i 2+ mobilization at the hFPR1.

Original languageEnglish
Pages (from-to)5242-5248
Number of pages7
JournalJournal of Medicinal Chemistry
Volume62
Issue number10
DOIs
Publication statusPublished - 23 May 2019

Cite this

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. / Substituted Pyridazin-3(2 H)-ones as Highly Potent and Biased Formyl Peptide Receptor Agonists. In: Journal of Medicinal Chemistry. 2019 ; Vol. 62, No. 10. pp. 5242-5248.
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abstract = "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 EC 50 of 0.083 μM for phosphorylation of ERK1/2 and an approximate 20-fold bias away from Ca i 2+ mobilization at the hFPR1.",
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Substituted Pyridazin-3(2 H)-ones as Highly Potent and Biased Formyl Peptide Receptor Agonists. / 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.

In: Journal of Medicinal Chemistry, Vol. 62, No. 10, 23.05.2019, p. 5242-5248.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Substituted Pyridazin-3(2 H)-ones as Highly Potent and Biased Formyl Peptide Receptor Agonists

AU - Deora, Girdhar Singh

AU - Qin, Cheng Xue

AU - Vecchio, Elizabeth A.

AU - Debono, Aaron J.

AU - Priebbenow, Daniel L.

AU - Brady, Ryan M.

AU - Beveridge, Julia

AU - Teguh, Silvia C.

AU - Deo, Minh

AU - May, Lauren T.

AU - Krippner, Guy

AU - Ritchie, Rebecca H.

AU - Baell, Jonathan B.

PY - 2019/5/23

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