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Free fatty acid receptor 3 (FFA3, previously GPR41) is activated by short-chain fatty acids, mediates health effects of the gut microbiota, and is a therapeutic target for metabolic and inflammatory diseases. The shortage of well-characterized tool compounds has however impeded progress. Herein, we report structure-activity relationship of an allosteric modulator series and characterization of physicochemical and pharmacokinetic properties of selected compounds, including previous and new tools. Two representatives, 57 (TUG-1907) and 63 (TUG-2015), showed improved solubility and preserved potency. Of these, 57 , with EC 50 = 145 nM and a solubility of 33 μM, showed high clearance in vivo but is a preferred tool in vitro. In contrast, 63 , with EC 50 = 162 nM and a solubility of 9 μM, showed lower clearance and seems better suited for in vivo studies. Using 57 , we demonstrate for the first time that FFA3 activation leads to calcium mobilization in murine dorsal root ganglia.

Structure–Activity Relationship Studies of Tetrahydroquinolone Free Fatty Acid Receptor 3 Modulators