Discovery of Potent Tetrazole Free Fatty Acid Receptor 2 Antagonists

[Image: see text] 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...

Descripción completa

Detalles Bibliográficos
Autores principales: Valentini, Alice, Schultz-Knudsen, Katrine, Højgaard Hansen, Anders, Tsakoumagkou, Argyro, Jenkins, Laura, Christensen, Henriette B., Manandhar, Asmita, Milligan, Graeme, Ulven, Trond, Rexen Ulven, Elisabeth
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2023
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10547238/
https://www.ncbi.nlm.nih.gov/pubmed/37129317
http://dx.doi.org/10.1021/acs.jmedchem.2c01935
Descripción
Sumario:[Image: see text] 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 IC(50) values of 3–4 nM in both cAMP and GTPγS assays, favorable physicochemical and pharmacokinetic properties, and the ability to completely inhibit propionate-induced neutrophil migration and respiratory burst.

Ejemplares similares