Discovery of a Potent and Selective Free Fatty Acid Receptor 1 Agonist with Low Lipophilicity and High Oral Bioavailability

• Published in: Journal of medicinal chemistry 2013-02, Vol.56 (3), p.982-992
• Main Authors: Christiansen, Elisabeth, Due-Hansen, Maria E, Urban, Christian, Grundmann, Manuel, Schmidt, Johannes, Hansen, Steffen V. F, Hudson, Brian D, Zaibi, Mohamed, Markussen, Stine B, Hagesaether, Ellen, Milligan, Graeme, Cawthorne, Michael A, Kostenis, Evi, Kassack, Matthias U, Ulven, Trond
• Format: Article
• Language: English
• Subjects: Administration, Oral; Animals; Biological Availability; Drug Discovery; Magnetic Resonance Spectroscopy; Mice; Models, Molecular; Receptors, G-Protein-Coupled - agonists; Receptors, G-Protein-Coupled - chemistry; Spectrometry, Mass, Electrospray Ionization; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm301470a

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.