Discovery of Potent Tetrazole Free Fatty Acid Receptor 2 Antagonists

Research output: Contribution to journal › Journal article › Research › peer-review

Standard

Discovery of Potent Tetrazole Free Fatty Acid Receptor 2 Antagonists. / Valentini, Alice; Schultz-Knudsen, Katrine; Hansen, Anders Højgaard; Tsakoumagkou, Argyro; Jenkins, Laura; Christensen, Henriette B.; Manandhar, Asmita; Milligan, Graeme; Ulven, Trond; Ulven, Elisabeth Rexen.

In: Journal of Medicinal Chemistry, Vol. 66, No. 9, 2023, p. 6105–6121.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Valentini, A, Schultz-Knudsen, K, Hansen, AH, Tsakoumagkou, A, Jenkins, L, Christensen, HB, Manandhar, A, Milligan, G, Ulven, T & Ulven, ER 2023, 'Discovery of Potent Tetrazole Free Fatty Acid Receptor 2 Antagonists', Journal of Medicinal Chemistry, vol. 66, no. 9, pp. 6105–6121. https://doi.org/10.1021/acs.jmedchem.2c01935

APA

Valentini, A., Schultz-Knudsen, K., Hansen, A. H., Tsakoumagkou, A., Jenkins, L., Christensen, H. B., Manandhar, A., Milligan, G., Ulven, T., & Ulven, E. R. (2023). Discovery of Potent Tetrazole Free Fatty Acid Receptor 2 Antagonists. Journal of Medicinal Chemistry, 66(9), 6105–6121. https://doi.org/10.1021/acs.jmedchem.2c01935

Vancouver

Valentini A, Schultz-Knudsen K, Hansen AH, Tsakoumagkou A, Jenkins L, Christensen HB et al. Discovery of Potent Tetrazole Free Fatty Acid Receptor 2 Antagonists. Journal of Medicinal Chemistry. 2023;66(9):6105–6121. https://doi.org/10.1021/acs.jmedchem.2c01935

Author

Valentini, Alice ; Schultz-Knudsen, Katrine ; Hansen, Anders Højgaard ; Tsakoumagkou, Argyro ; Jenkins, Laura ; Christensen, Henriette B. ; Manandhar, Asmita ; Milligan, Graeme ; Ulven, Trond ; Ulven, Elisabeth Rexen. / Discovery of Potent Tetrazole Free Fatty Acid Receptor 2 Antagonists. In: Journal of Medicinal Chemistry. 2023 ; Vol. 66, No. 9. pp. 6105–6121.

Bibtex

@article{6099c27768784f26ab28860be184e7da,
title = "Discovery of Potent Tetrazole Free Fatty Acid Receptor 2 Antagonists",
abstract = "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.",
keywords = "FFA2 ANTAGONIST, FUNCTIONAL-CHARACTERIZATION, GLUCOSE-TOLERANCE, GUT MICROBIOTA, DIETARY FIBER, AGONIST, GPR43, IDENTIFICATION, GLPG0974, SAFETY",
author = "Alice Valentini and Katrine Schultz-Knudsen and Hansen, {Anders H{\o}jgaard} and Argyro Tsakoumagkou and Laura Jenkins and Christensen, {Henriette B.} and Asmita Manandhar and Graeme Milligan and Trond Ulven and Ulven, {Elisabeth Rexen}",
year = "2023",
doi = "10.1021/acs.jmedchem.2c01935",
language = "English",
volume = "66",
pages = "6105–6121",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "9",

}

RIS

TY - JOUR

T1 - Discovery of Potent Tetrazole Free Fatty Acid Receptor 2 Antagonists

AU - Valentini, Alice

AU - Schultz-Knudsen, Katrine

AU - Hansen, Anders Højgaard

AU - Tsakoumagkou, Argyro

AU - Jenkins, Laura

AU - Christensen, Henriette B.

AU - Manandhar, Asmita

AU - Milligan, Graeme

AU - Ulven, Trond

AU - Ulven, Elisabeth Rexen

PY - 2023

Y1 - 2023

N2 - 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.

AB - 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.

KW - FFA2 ANTAGONIST

KW - FUNCTIONAL-CHARACTERIZATION

KW - GLUCOSE-TOLERANCE

KW - GUT MICROBIOTA

KW - DIETARY FIBER

KW - AGONIST

KW - GPR43

KW - IDENTIFICATION

KW - GLPG0974

KW - SAFETY

U2 - 10.1021/acs.jmedchem.2c01935

DO - 10.1021/acs.jmedchem.2c01935

M3 - Journal article

C2 - 37129317

VL - 66

SP - 6105

EP - 6121

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 9

ER -

ID: 348205126