Discovery of Potent Tetrazole Free Fatty Acid Receptor 2 Antagonists

Alice Valentini; Katrine Schultz-Knudsen; Anders Højgaard Hansen; Argyro Tsakoumagkou; Laura Jenkins; Henriette B. Christensen; Asmita Manandhar; Graeme Milligan; Trond Ulven; Elisabeth Rexen Ulven

doi:10.1021/acs.jmedchem.2c01935

Discovery of Potent Tetrazole Free Fatty Acid Receptor 2 Antagonists

Alice Valentini, Katrine Schultz-Knudsen, Anders Højgaard Hansen, Argyro Tsakoumagkou, Laura Jenkins, Henriette B. Christensen, Asmita Manandhar, Graeme Milligan, Trond Ulven, Elisabeth Rexen Ulven^*

^*Corresponding author af dette arbejde

Medicinalkemi

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

2 Citationer (Scopus)

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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.

Originalsprog	Engelsk
Tidsskrift	Journal of Medicinal Chemistry
Vol/bind	66
Udgave nummer	9
Sider (fra-til)	6105–6121
ISSN	0022-2623
DOI	https://doi.org/10.1021/acs.jmedchem.2c01935
Status	Udgivet - 2023

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10.1021/acs.jmedchem.2c01935Licens: CC BY

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Citationsformater

@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",

}

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

SN - 0022-2623

VL - 66

SP - 6105

EP - 6121

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 9

ER -