Identification of a Potent and Selective Free Fatty Acid Receptor 1 (FFA1/GPR40) Agonist with Favorable Physicochemical and in Vitro ADME Properties

• Published in: Journal of medicinal chemistry Vol. 54; no. 19; pp. 6691 - 6703
• Main Authors: Christiansen, Elisabeth, Urban, Christian, Grundmann, Manuel, Due-Hansen, Maria E, Hagesaether, Ellen, Schmidt, Johannes, Pardo, Leonardo, Ullrich, Susanne, Kostenis, Evi, Kassack, Matthias, Ulven, Trond
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 13.10.2011; Amer Chemical Soc
• Subjects: Animals; Cell Line, Tumor; Cell Membrane Permeability; Chemistry, Medicinal; Diabetes Mellitus, Type 2 - drug therapy; Humans; Hypoglycemic Agents - chemical synthesis; Hypoglycemic Agents - metabolism; Hypoglycemic Agents - pharmacology; In Vitro Techniques; Insulin - metabolism; Insulin Secretion; Life Sciences & Biomedicine; Microsomes, Liver - metabolism; Models, Molecular; Pharmacology & Pharmacy; Phenylpropionates - chemical synthesis; Phenylpropionates - metabolism; Phenylpropionates - pharmacology; Pyridines - chemical synthesis; Pyridines - metabolism; Pyridines - pharmacology; Rats; Receptors, G-Protein-Coupled - agonists; Recombinant Proteins - agonists; Science & Technology; Structure-Activity Relationship; STIMULATION; PROTEIN-COUPLED RECEPTOR; SMALL-MOLECULE; GPR40 AGONIST; GLUCOSE; INSULIN-SECRETION; DRUG DISCOVERY; PANCREATIC BETA-CELLS; MICE; ANTAGONISTS
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm2005699

The free fatty acid receptor 1 (FFA1, also known as GPR40) enhances glucose-stimulated insulin secretion from pancreatic β-cells and is recognized as an interesting new target for treatment of type 2 diabetes. Several series of selective FFA1 agonists are already known. Most of these are derived from free fatty acids (FFAs) or glitazones and are relatively lipophilic. Aiming for the development of potent, selective, and less lipophilic FFA1 agonists, the terminal phenyl of a known compound series was replaced by nitrogen containing heterocycles. This resulted in the identification of 37, a selective FFA1 agonist with potent activity on recombinant human FFA1 receptors and on the rat insulinoma cell line INS-1E, optimal lipophilicity, and excellent in vitro permeability and metabolic stability.