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 -