title: Discovery of a potent and selective free fatty acid receptor 1 agonist with low lipophilicity and high oral bioavailability.
abstract: The free fatty acid receptor 1 (FFA1, also known as GPR40) mediates enhancement of glucose-stimulated insulin secretion and is emerging as a new target for the treatment of type 2 diabetes. Several FFA1 agonists are known, but the majority of these suffer from high lipophilicity. We have previously reported the FFA1 agonist 3 (TUG-424). We here describe the continued structure-activity exploration and optimization of this compound series, leading to the discovery of the more potent agonist 40, a compound with low lipophilicity, excellent in vitro metabolic stability and permeability, complete oral bioavailability, and appreciable efficacy on glucose tolerance in mice.
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.forename: Maria E
authors.initials: ME
authors.lastname: Due-Hansen
authors.forename: Christian
authors.initials: C
authors.lastname: Urban
authors.forename: Manuel
authors.initials: M
authors.lastname: Grundmann
authors.forename: Johannes
authors.initials: J
authors.lastname: Schmidt
authors.forename: Steffen V F
authors.initials: SV
authors.lastname: Hansen
authors.forename: Brian D
authors.initials: BD
authors.lastname: Hudson
authors.forename: Mohamed
authors.initials: M
authors.lastname: Zaibi
authors.forename: Stine B
authors.initials: SB
authors.lastname: Markussen
authors.forename: Ellen
authors.initials: E
authors.lastname: Hagesaether
authors.forename: Graeme
authors.initials: G
authors.lastname: Milligan
authors.forename: Michael A
authors.initials: MA
authors.lastname: Cawthorne
authors.forename: Evi
authors.initials: E
authors.lastname: Kostenis
authors.forename: Matthias U
authors.initials: MU
authors.lastname: Kassack
authors.forename: Trond
authors.initials: T
authors.lastname: Ulven
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D055808:Drug Discovery; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008958:Models, Molecular; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000737:chemistry; D021241:Spectrometry, Mass, Electrospray Ionization; D013329:Structure-Activity Relationship
chemical_list: C473034:FFAR1 protein, human; D043562:Receptors, G-Protein-Coupled