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

被引：19

作者：

Deora, Girdhar Singh ^{[2
]}

Qin, Cheng Xue ^{[3
,4
]}

Vecchio, Elizabeth A. ^{[3
]}

Debono, Aaron J. ^{[2
]}

Priebbenow, Daniel L. ^{[2
]}

Brady, Ryan M. ^{[2
]}

Beveridge, Julia ^{[2
]}

Teguh, Silvia C. ^{[2
]}

Minh Deo ^{[3
]}

May, Lauren T. ^{[5
]}

Krippner, Guy ^{[3
]}

Ritchie, Rebecca H. ^{[3
,4
,6
]}

Baell, Jonathan B. ^{[1
,2
,7
]}

机构：

[1] Nanjing Tech Univ, Sch Pharmaceut Sci, Nanjing 211816, Jiangsu, Peoples R China

[2] Monash Univ, Monash Inst Pharmaceut Sci, Med Chem, Parkville, Vic 3052, Australia

[3] Baker Heart & Diabet Inst, 7S Commercial Rd, Melbourne, Vic 3004, Australia

[4] Univ Melbourne, Dept Pharmacol & Therapeut, Melbourne, Vic 3010, Australia

[5] Monash Univ, Monash Inst Pharmaceut Sci, Drug Discovery Biol, Parkville, Vic 3052, Australia

[6] Monash Univ, Dept Diabet, Cent Clin Sch, Melbourne, Vic 3004, Australia

[7] Monash Univ, ARC Ctr Fragment Based Design, Parkville, Vic 3052, Australia

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2019年 / 62卷 / 10期

基金：

英国医学研究理事会; 澳大利亚国家健康与医学研究理事会;

关键词：

FUNCTIONAL SELECTIVITY; REPERFUSION INJURY; RESOLUTION; TARGET;

D O I：

10.1021/acs.jmedchem.8b01912

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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 EC50 of 0.083 mu M for phosphorylation of ERK1/2 and an approximate 20-fold bias away from Ca-i(2+) mobilization at the hFPR1.

引用

页码：5242 / 5248

页数：7

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