Discovery of Potent Tetrazole Free Fatty Acid Receptor 2 Antagonists

被引：2

作者：

Valentini, Alice ^{[3
]}

Schultz-Knudsen, Katrine ^{[3
]}

Hansen, Anders Hojgaard ^{[2
]}

Tsakoumagkou, Argyro ^{[3
]}

Jenkins, Laura ^{[1
]}

Christensen, Henriette B. ^{[2
]}

Manandhar, Asmita ^{[3
]}

Milligan, Graeme ^{[1
]}

Ulven, Trond ^{[2
,3
]}

Ulven, Elisabeth Rexen ^{[3
]}

机构：

[1] Univ Glasgow, Coll Med Vet & Life Sci, Ctr Translat Pharmacol, Sch Mol Biosci, Glasgow G12 8QQ, Scotland

[2] Univ Southern Denmark, Dept Phys Chem & Pharm, DK-5230 Odense M, Denmark

[3] Univ Copenhagen, Dept Drug Design & Pharmacol, DK-2100 Copenhagen, Denmark

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2023年 / 66卷 / 09期

基金：

英国生物技术与生命科学研究理事会;

关键词：

FFA2; ANTAGONIST; FUNCTIONAL-CHARACTERIZATION; GLUCOSE-TOLERANCE; GUT MICROBIOTA; DIETARY FIBER; AGONIST; GPR43; IDENTIFICATION; GLPG0974; SAFETY;

D O I：

10.1021/acs.jmedchem.2c01935

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The free fatty acid receptor 2 (FFA2), also known as GPR43, mediates effects of short-chain fatty acids and has attracted interest as a potential target for treatment of various metabolic and inflammatory diseases. Herein, we report the results from bioisosteric replacement of the carboxylic acid group of the established FFA2 antagonist CATPB and SAR investigations around these compounds, leading to the discovery of the first high potency FFA2 antagonists, with the preferred compound TUG 2304 (16l) featuring IC50 values of 3-4 nM in both cAMP and GTP gamma S assays, favorable physicochemical and pharmacokinetic properties, and the ability to completely inhibit propionate induced neutrophil migration and respiratory burst.

引用

页码：6105 / 6121

页数：17

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