Journal article

Substituted Pyridazin-3(2H)-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, Deo Minh, Lauren T May, Guy Krippner, Rebecca H Ritchie, Jonathan B Baell

JOURNAL OF MEDICINAL CHEMISTRY | AMER CHEMICAL SOC | Published : 2019

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.

Grants

Awarded by National Health and Medical Research Council (NHMRC) of Australia


Awarded by National Health and Medical Research Council of Australia (NHMRC)


Awarded by NHMRC


Funding Acknowledgements

This work was supported in part by the National Health and Medical Research Council (NHMRC) of Australia (APP1045140 and APP1120853). The National Health and Medical Research Council of Australia (NHMRC) is thanked for Fellowship support for JBB (2012-2016 Senior Research Fellowship APP1020411, 2017-Principal Research Fellowship APP1117602) and RHR (Senior Research Fellowship APP1059960). CXQ is a Baker Fellow. EAV is NHMRC Early Career fellow (APP1145769). Acknowledged is Australian Federal Government Education Investment Fund Super Science Initiative and the Victorian State Government, Victoria Science Agenda Investment Fund for infrastructure support, and the facilities, and the scientific and technical assistance of the Australian Translational Medicinal Chemistry Facility (ATMCF). ATMCF is supported by Australian Government's National Collaborative Research Infrastructure Strategy (NCRIS) program via Therapeutic Innovation Australia (TIA).