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

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 EC50 = 145 nM and a solubility
of 33 μM, showed high clearance in vivo but is a preferred tool
in vitro. In contrast, 63, with EC50 = 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.