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Structure-Activity Relationship Explorations and Discovery of a Potent Antagonist for the Free Fatty Acid Receptor 2 |
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| Authors: | Dr Anders Højgaard Hansen Henriette B Christensen Dr Sunil K Pandey Dr Eugenia Sergeev Alice Valentini Julia Dunlop Domonkos Dedeo Simone Fratta Dr Brian D Hudson Prof Graeme Milligan Prof Trond Ulven Prof Elisabeth Rexen Ulven |
| Affiliation: | 1. Department of Physics, Chemistry and Pharmacy, University of Southern Denmark, Campusvej 55, 5230 Odense M, Denmark
These authors contributed equally to this work.;2. Department of Physics, Chemistry and Pharmacy, University of Southern Denmark, Campusvej 55, 5230 Odense M, Denmark;3. 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;4. Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark |
| 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. |
| Keywords: | FFA2 GPR43 GPCR short-chain fatty acids inflammation |