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 | |
| Publication status | Published - 23 May 2019 |
Cite this
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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 journal › Article › Research › peer-review
TY - JOUR
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
Y1 - 2019/5/23
N2 - 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.
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.
UR - http://www.scopus.com/inward/record.url?scp=85066051060&partnerID=8YFLogxK
U2 - 10.1021/acs.jmedchem.8b01912
DO - 10.1021/acs.jmedchem.8b01912
M3 - Article
VL - 62
SP - 5242
EP - 5248
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 10
ER -