title: Discovery of a Potent Free Fatty Acid 1 Receptor Agonist with Low Lipophilicity, Low Polar Surface Area, and Robust in Vivo Efficacy.
abstract: The free fatty acid receptor 1 (FFA1 or GPR40) is established as an interesting potential target for treatment of type 2 diabetes. However, to obtain optimal ligands, it may be necessary to limit both lipophilicity and polar surface area, translating to a need for small compounds. We here describe the identification of 24, a potent FFA1 agonist with low lipophilicity and very high ligand efficiency that exhibit robust glucose lowering effect.
authors.affiliation: Department of Physics, Chemistry and Pharmacy, University of Southern Denmark , Campusvej 55, DK-5230 Odense M, Denmark.
authors.forename: Steffen V F
authors.initials: SV
authors.lastname: Hansen
authors.affiliation: Department of Physics, Chemistry and Pharmacy, University of Southern Denmark , Campusvej 55, DK-5230 Odense M, Denmark.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Christiansen
authors.affiliation: Institute of Pharmaceutical and Medicinal Chemistry, University of Düsseldorf , Universitätsstrasse 1, D-40225 Düsseldorf, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Urban
authors.affiliation: Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow , Glasgow G12 8QQ, Scotland, U.K.
authors.forename: Brian D
authors.initials: BD
authors.lastname: Hudson
authors.affiliation: Clore Laboratory, University of Buckingham , Hunter Street, Buckingham MK18 1EG, U.K.
authors.forename: Claire J
authors.initials: CJ
authors.lastname: Stocker
authors.affiliation: Department of Physics, Chemistry and Pharmacy, University of Southern Denmark , Campusvej 55, DK-5230 Odense M, Denmark.
authors.forename: Maria E
authors.initials: ME
authors.lastname: Due-Hansen
authors.affiliation: Clore Laboratory, University of Buckingham , Hunter Street, Buckingham MK18 1EG, U.K.
authors.forename: Ed T
authors.initials: ET
authors.lastname: Wargent
authors.affiliation: Department of Physics, Chemistry and Pharmacy, University of Southern Denmark , Campusvej 55, DK-5230 Odense M, Denmark.
authors.forename: Bharat
authors.initials: B
authors.lastname: Shimpukade
authors.affiliation: Department of Biochemistry and Molecular Biology, VILLUM Center for Bioanalytical Sciences, University of Southern Denmark , Campusvej 55, DK-5230 Odense M, Denmark.
authors.forename: Reinaldo
authors.initials: R
authors.lastname: Almeida
authors.affiliation: Department of Biochemistry and Molecular Biology, VILLUM Center for Bioanalytical Sciences, University of Southern Denmark , Campusvej 55, DK-5230 Odense M, Denmark.
authors.forename: Christer S
authors.initials: CS
authors.lastname: Ejsing
authors.affiliation: Clore Laboratory, University of Buckingham , Hunter Street, Buckingham MK18 1EG, U.K.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Cawthorne
authors.affiliation: Institute of Pharmaceutical and Medicinal Chemistry, University of Düsseldorf , Universitätsstrasse 1, D-40225 Düsseldorf, Germany.
authors.forename: Matthias U
authors.initials: MU
authors.lastname: Kassack
authors.affiliation: Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow , Glasgow G12 8QQ, Scotland, U.K.
authors.forename: Graeme
authors.initials: G
authors.lastname: Milligan
authors.affiliation: Department of Physics, Chemistry and Pharmacy, University of Southern Denmark , Campusvej 55, DK-5230 Odense M, Denmark.
authors.forename: Trond
authors.initials: T
authors.lastname: Ulven
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D055808:Drug Discovery; D005951:Glucose Tolerance Test; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D008024:Ligands; D008055:Lipids / Q000737:chemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D010666:Phenylpropionates / Q000138:chemical synthesis* / Q000494:pharmacology*; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*; D013329:Structure-Activity Relationship
chemical_list: C000609917:3-(2-fluoro-4-(3-methylpent-3-en-1-yn-1-yl)phenyl)propanoic acid; D001786:Blood Glucose; C473036:Ffar1 protein, mouse; D007004:Hypoglycemic Agents; D008024:Ligands; D008055:Lipids; D010666:Phenylpropionates; D043562:Receptors, G-Protein-Coupled