Polar aromatic periphery increases agonist potency of spirocyclic free fatty acid receptor (GPR40) agonists inspired by LY2881835

• DOI: 10.1016/j.ejmech.2017.01.005
• Publication Date: 2017-01-05T13:44:06Z
• Authors: Mikhail Krasavin; Alexey Lukin; Daria Bagnyukova; Nikolay Zhurilo; Aleksei Golovanov; Sergey Zozulya; Ihor Zahanich; Daniel Moore; Irina G. Tikhonova
• Keywords: 0301 basic medicine; Protein Conformation; CHO Cells; 540; name=SDG 3 - Good Health and Well-being; Receptors, G-Protein-Coupled; Molecular Docking Simulation; Structure-Activity Relationship; 03 medical and health sciences; Cricetulus; Piperidines; 615; Cricetinae; Drug Design; /dk/atira/pure/sustainabledevelopmentgoals/good_health_and_well_being; Animals; Humans; Hypoglycemic Agents; Spiro Compounds; /dk/atira/pure/sustainabledevelopmentgoals/good_health_and_well_being; name=SDG 3 - Good Health and Well-being; Caco-2 Cells

A series of spirocyclic compounds inspired by Eli Lilly's phase 1 antidiabetic FFA1 receptor agonist LY2881835 was designed to include polar aromatic periphery groups and explore a possibility of building additional contacts with the target near the agonist binding site. The frontrunner compound in the series (9i) was shown to be a potent (EC50 = 260 nM) FFA1 agonist with excellent aqueous (PBS) solubility and good Caco-2 permeability. The observed structure-activity relationships were rationalized by a docking study. The new series significantly expands the ligand landscape for the ongoing quest for new potent and more polar FFA1 agonists as fundamentally new class of therapeutic agents against type 2 diabetes mellitus.