Structure-Activity Relationship Explorations and Discovery of a Potent Antagonist for the Free Fatty Acid Receptor 2
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.
Search for more papers by this authorHenriette 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.
Search for more papers by this authorDr. Sunil K. Pandey
Department of Physics, Chemistry and Pharmacy, University of Southern Denmark, Campusvej 55, 5230 Odense M, Denmark
Search for more papers by this authorDr. 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
Search for more papers by this authorAlice Valentini
Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark
Search for more papers by this authorJulia 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
Search for more papers by this authorDomonkos 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
Search for more papers by this authorSimone Fratta
Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark
Search for more papers by this authorDr. 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
Search for more papers by this authorProf. 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
Search for more papers by this authorCorresponding 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
Search for more papers by this authorCorresponding Author
Prof. Elisabeth Rexen Ulven
Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark
Search for more papers by this authorDr. 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.
Search for more papers by this authorHenriette 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.
Search for more papers by this authorDr. Sunil K. Pandey
Department of Physics, Chemistry and Pharmacy, University of Southern Denmark, Campusvej 55, 5230 Odense M, Denmark
Search for more papers by this authorDr. 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
Search for more papers by this authorAlice Valentini
Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark
Search for more papers by this authorJulia 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
Search for more papers by this authorDomonkos 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
Search for more papers by this authorSimone Fratta
Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark
Search for more papers by this authorDr. 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
Search for more papers by this authorProf. 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
Search for more papers by this authorCorresponding 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
Search for more papers by this authorCorresponding Author
Prof. Elisabeth Rexen Ulven
Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark
Search for more papers by this authorGraphical 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.
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