title: Structure-Activity Study of Dihydrocinnamic Acids and Discovery of the Potent FFA1 (GPR40) Agonist TUG-469.
abstract: The free fatty acid 1 receptor (FFA1 or GPR40), which is highly expressed on pancreatic β-cells and amplifies glucose-stimulated insulin secretion, has emerged as an attractive target for the treatment of type 2 diabetes. Several FFA1 agonists containing the para-substituted dihydrocinnamic acid moiety are known. We here present a structure-activity relationship study of this compound family suggesting that the central methyleneoxy linker is preferable for the smaller compounds, whereas the central methyleneamine linker gives higher potency to the larger compounds. The study resulted in the discovery of the potent and selective full FFA1 agonist TUG-469 (29).
authors.affiliation: Department of Physics and Chemistry, University of Southern Denmark, Campusvej 55, DK-5230 Odense M, Denmark.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Christiansen
authors.affiliation: Department of Physics and Chemistry, University of Southern Denmark, Campusvej 55, DK-5230 Odense M, Denmark.
authors.forename: Maria E
authors.initials: ME
authors.lastname: Due-Hansen
authors.affiliation: Pharmaceutical Biochemistry, 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: Department of Molecular, Cellular and Pharmacobiology Institute for Pharmaceutical Biology, University of Bonn, Nussallee 6, D-53115 Bonn, Germany.
authors.forename: Nicole
authors.initials: N
authors.lastname: Merten
authors.affiliation: Department of Internal Medicine, Division of Endocrinology, Diabetology, Vascular Medicine, Nephrology and Clinical Chemistry, University of Tübingen, Otfried-Müller-Strasse 10, D-72076 Tübingen, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Pfleiderer
authors.affiliation: Department of Physics and Chemistry, University of Southern Denmark, Campusvej 55, DK-5230 Odense M, Denmark.
authors.forename: Kasper K
authors.initials: KK
authors.lastname: Karlsen
authors.affiliation: Department of Physics and Chemistry, University of Southern Denmark, Campusvej 55, DK-5230 Odense M, Denmark.
authors.forename: Sanne S
authors.initials: SS
authors.lastname: Rasmussen
authors.affiliation: Department of Physics and Chemistry, University of Southern Denmark, Campusvej 55, DK-5230 Odense M, Denmark.
authors.forename: Mette
authors.initials: M
authors.lastname: Steensgaard
authors.affiliation: Pharmaceutical Biochemistry, Institute of Pharmaceutical and Medicinal Chemistry, University of Düsseldorf, Universitätsstrasse 1, D-40225 Düsseldorf, Germany.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Hamacher
authors.affiliation: Department of Molecular, Cellular and Pharmacobiology Institute for Pharmaceutical Biology, University of Bonn, Nussallee 6, D-53115 Bonn, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Schmidt
authors.affiliation: Department of Molecular, Cellular and Pharmacobiology Institute for Pharmaceutical Biology, University of Bonn, Nussallee 6, D-53115 Bonn, Germany.
authors.forename: Christel
authors.initials: C
authors.lastname: Drewke
authors.affiliation: Department of Biology, University of Copenhagen, Ole Maaløes Vej 5, DK-2200 Copenhagen N, Denmark.
authors.forename: Rasmus Koefoed
authors.initials: RK
authors.lastname: Petersen
authors.affiliation: Department of Biology, University of Copenhagen, Ole Maaløes Vej 5, DK-2200 Copenhagen N, Denmark.
authors.forename: Karsten
authors.initials: K
authors.lastname: Kristiansen
authors.affiliation: Department of Internal Medicine, Division of Endocrinology, Diabetology, Vascular Medicine, Nephrology and Clinical Chemistry, University of Tübingen, Otfried-Müller-Strasse 10, D-72076 Tübingen, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Ullrich
authors.affiliation: Department of Molecular, Cellular and Pharmacobiology Institute for Pharmaceutical Biology, University of Bonn, Nussallee 6, D-53115 Bonn, Germany.
authors.forename: Evi
authors.initials: E
authors.lastname: Kostenis
authors.affiliation: Pharmaceutical Biochemistry, 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: Department of Physics and Chemistry, University of Southern Denmark, Campusvej 55, DK-5230 Odense M, Denmark.
authors.forename: Trond
authors.initials: T
authors.lastname: Ulven
keywords: Diabetes; FFA1; FFAR1; GPR40; drug discovery; fatty acids