Volume 16, Issue 21 p. 3326-3341
Full Paper

Structure-Activity Relationship Explorations and Discovery of a Potent Antagonist for the Free Fatty Acid Receptor 2

Dr. Anders Højgaard Hansen

Dr. Anders Højgaard Hansen

Department of Physics, Chemistry and Pharmacy, University of Southern Denmark, Campusvej 55, 5230 Odense M, Denmark

These authors contributed equally to this work.

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Henriette B. Christensen

Henriette B. Christensen

Department of Physics, Chemistry and Pharmacy, University of Southern Denmark, Campusvej 55, 5230 Odense M, Denmark

These authors contributed equally to this work.

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Dr. Sunil K. Pandey

Dr. Sunil K. Pandey

Department of Physics, Chemistry and Pharmacy, University of Southern Denmark, Campusvej 55, 5230 Odense M, Denmark

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Dr. Eugenia Sergeev

Dr. Eugenia Sergeev

Centre for Translational Pharmacology, Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, G12 8QQ Scotland, UK

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Alice Valentini

Alice Valentini

Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark

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Julia Dunlop

Julia Dunlop

Centre for Translational Pharmacology, Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, G12 8QQ Scotland, UK

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Domonkos Dedeo

Domonkos Dedeo

Centre for Translational Pharmacology, Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, G12 8QQ Scotland, UK

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Simone Fratta

Simone Fratta

Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark

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Dr. Brian D. Hudson

Dr. Brian D. Hudson

Centre for Translational Pharmacology, Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, G12 8QQ Scotland, UK

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Prof. Graeme Milligan

Prof. Graeme Milligan

Centre for Translational Pharmacology, Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, G12 8QQ Scotland, UK

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Prof. Trond Ulven

Corresponding Author

Prof. Trond Ulven

Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark

Department of Physics, Chemistry and Pharmacy, University of Southern Denmark, Campusvej 55, 5230 Odense M, Denmark

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Prof. Elisabeth Rexen Ulven

Corresponding Author

Prof. Elisabeth Rexen Ulven

Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark

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First published: 19 July 2021
Citations: 1

Graphical Abstract

Antagonist as the hero: The short-chain fatty acid receptor FFA2 is a promising drug target for metabolic and inflammatory diseases. Herein we present the SAR exploration of an antagonist series, leading to the discovery of a more potent antagonist with favorable solubility and pharmacokinetic properties.

Abstract

Free fatty acid receptor 2 (FFA2) is a sensor for short-chain fatty acids that has been identified as an interesting potential drug target for treatment of metabolic and inflammatory diseases. Although several ligand series are known for the receptor, there is still a need for improved compounds. One of the most potent and frequently used antagonists is the amide-substituted phenylbutanoic acid known as CATPB (1). We here report the structure-activity relationship exploration of this compound, leading to the identification of homologues with increased potency. The preferred compound 37 (TUG-1958) was found, besides improved potency, to have high solubility and favorable pharmacokinetic properties.

Conflict of interest

The authors declare no conflict of interest.