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

doi:10.1021/acs.jmedchem.8b01912

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 journal › Article › Research › peer-review

14 Citations (Scopus)

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 language	English
Pages (from-to)	5242-5248
Number of pages	7
Journal	Journal of Medicinal Chemistry
Volume	62
Issue number	10
DOIs	https://doi.org/10.1021/acs.jmedchem.8b01912
Publication status	Published - 23 May 2019

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Deora, G. S., Qin, C. X., Vecchio, E. A., Debono, A. J., Priebbenow, D. L., Brady, R. M., Beveridge, J., Teguh, S. C., Deo, M., May, L. T., Krippner, G., Ritchie, R. H., & Baell, J. B. (2019). Substituted Pyridazin-3(2 H)-ones as Highly Potent and Biased Formyl Peptide Receptor Agonists. Journal of Medicinal Chemistry, 62(10), 5242-5248. https://doi.org/10.1021/acs.jmedchem.8b01912

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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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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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AB - 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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IS - 10

ER -

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

Abstract

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