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...

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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
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author Valentini, Alice
Schultz-Knudsen, Katrine
Højgaard Hansen, Anders
Tsakoumagkou, Argyro
Jenkins, Laura
Christensen, Henriette B.
Manandhar, Asmita
Milligan, Graeme
Ulven, Trond
Rexen Ulven, Elisabeth
author_facet Valentini, Alice
Schultz-Knudsen, Katrine
Højgaard Hansen, Anders
Tsakoumagkou, Argyro
Jenkins, Laura
Christensen, Henriette B.
Manandhar, Asmita
Milligan, Graeme
Ulven, Trond
Rexen Ulven, Elisabeth
author_sort Valentini, Alice
collection PubMed
description [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.
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spelling pubmed-105472382023-10-04 Discovery of Potent Tetrazole Free Fatty Acid Receptor 2 Antagonists Valentini, Alice Schultz-Knudsen, Katrine Højgaard Hansen, Anders Tsakoumagkou, Argyro Jenkins, Laura Christensen, Henriette B. Manandhar, Asmita Milligan, Graeme Ulven, Trond Rexen Ulven, Elisabeth J Med Chem [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. American Chemical Society 2023-05-02 /pmc/articles/PMC10547238/ /pubmed/37129317 http://dx.doi.org/10.1021/acs.jmedchem.2c01935 Text en © 2023 American Chemical Society https://creativecommons.org/licenses/by/4.0/Permits the broadest form of re-use including for commercial purposes, provided that author attribution and integrity are maintained (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Valentini, Alice
Schultz-Knudsen, Katrine
Højgaard Hansen, Anders
Tsakoumagkou, Argyro
Jenkins, Laura
Christensen, Henriette B.
Manandhar, Asmita
Milligan, Graeme
Ulven, Trond
Rexen Ulven, Elisabeth
Discovery of Potent Tetrazole Free Fatty Acid Receptor 2 Antagonists
title Discovery of Potent Tetrazole Free Fatty Acid Receptor 2 Antagonists
title_full Discovery of Potent Tetrazole Free Fatty Acid Receptor 2 Antagonists
title_fullStr Discovery of Potent Tetrazole Free Fatty Acid Receptor 2 Antagonists
title_full_unstemmed Discovery of Potent Tetrazole Free Fatty Acid Receptor 2 Antagonists
title_short Discovery of Potent Tetrazole Free Fatty Acid Receptor 2 Antagonists
title_sort discovery of potent tetrazole free fatty acid receptor 2 antagonists
url 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
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