Open AccessStructure–Activity Relationship Studies of Tetrahydroquinolone Free Fatty Acid Receptor 3 Modulators
Author(s) -
Elisabeth Rexen Ulven,
Tezz Quon,
Eugenia Sergeev,
Natasja Barki,
Matjaž Brvar,
Brian D. Hudson,
Palash Dutta,
Anders Højgaard Hansen,
Line Ø. Bielefeldt,
Andrew B. Tobin,
Christine J. McKenzie,
Graeme Milligan,
Trond Ulven
Publication year - 2020
Publication title -
journal of medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.01
H-Index - 261
eISSN - 1520-4804
pISSN - 0022-2623
DOI - 10.1021/acs.jmedchem.9b02036
Subject(s) - chemistry , structure–activity relationship , fatty acid , biochemistry , receptor , stereochemistry , in vitro
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.
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