title: Non-Acidic Free Fatty Acid Receptor 4 Agonists with Antidiabetic Activity.
abstract: The free fatty acid receptor 4 (FFA4 or GPR120) has appeared as an interesting potential target for the treatment of metabolic disorders. At present, most FFA4 ligands are carboxylic acids that are assumed to mimic the endogenous long-chain fatty acid agonists. Here, we report preliminary structure-activity relationship studies of a previously disclosed nonacidic sulfonamide FFA4 agonist. Mutagenesis studies indicate that the compounds are orthosteric agonists despite the absence of a carboxylate function. The preferred compounds showed full agonist activity on FFA4 and complete selectivity over FFA1, although a significant fraction of these noncarboxylic acids also showed partial antagonistic activity on FFA1. Studies in normal and diet-induced obese (DIO) mice with the preferred compound 34 showed improved glucose tolerance after oral dosing in an oral glucose tolerance test. Chronic dosing of 34 in DIO mice resulted in significantly increased insulin sensitivity and a moderate but significant reduction in bodyweight, effects that were also present in mice lacking FFA1 but absent in mice lacking FFA4.
authors: Department of Physics, Chemistry and Pharmacy, University of Southern Denmark , Campusvej 55, DK-5230 Odense M, Denmark.
authors: Carlos M G
authors: CM
authors: Azevedo
authors: Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow , Glasgow G12 8QQ, Scotland, U.K.
authors: Kenneth R
authors: KR
authors: Watterson
authors: Buckingham Institute for Translational Medicine, University of Buckingham , Hunter Street, Buckingham MK18 1EG, U.K.
authors: Ed T
authors: ET
authors: Wargent
authors: Department of Physics, Chemistry and Pharmacy, University of Southern Denmark , Campusvej 55, DK-5230 Odense M, Denmark.
authors: Steffen V F
authors: SV
authors: Hansen
authors: Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow , Glasgow G12 8QQ, Scotland, U.K.
authors: Brian D
authors: BD
authors: Hudson
authors: Buckingham Institute for Translational Medicine, University of Buckingham , Hunter Street, Buckingham MK18 1EG, U.K.
authors: Małgorzata A
authors: MA
authors: Kępczyńska
authors: Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow , Glasgow G12 8QQ, Scotland, U.K.
authors: Julia
authors: J
authors: Dunlop
authors: Department of Physics, Chemistry and Pharmacy, University of Southern Denmark , Campusvej 55, DK-5230 Odense M, Denmark.
authors: Bharat
authors: B
authors: Shimpukade
authors: Department of Physics, Chemistry and Pharmacy, University of Southern Denmark , Campusvej 55, DK-5230 Odense M, Denmark.
authors: Elisabeth
authors: E
authors: Christiansen
authors: Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow , Glasgow G12 8QQ, Scotland, U.K.
authors: Graeme
authors: G
authors: Milligan
authors: Buckingham Institute for Translational Medicine, University of Buckingham , Hunter Street, Buckingham MK18 1EG, U.K.
authors: Claire J
authors: CJ
authors: Stocker
authors: Department of Physics, Chemistry and Pharmacy, University of Southern Denmark , Campusvej 55, DK-5230 Odense M, Denmark.
authors: Trond
authors: T
authors: Ulven
mesh_terms: D000818:Animals; D002460:Cell Line; D005951:Glucose Tolerance Test; D006801:Humans; D007004:Hypoglycemic Agents / Q000737:chemistry* / Q000494:pharmacology*; D007333:Insulin Resistance; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: C519853:FFAR4 protein, human; D007004:Hypoglycemic Agents; D043562:Receptors, G-Protein-Coupled; D013449:Sulfonamides