Structure-activity relationship studies of tetrahydroquinolone free fatty acid receptor 3 modulators

Rexen Ulven, E. et al. (2020) Structure-activity relationship studies of tetrahydroquinolone free fatty acid receptor 3 modulators. Journal of Medicinal Chemistry, 63(7), pp. 3577-3595. (doi: 10.1021/acs.jmedchem.9b02036) (PMID:32141297) (PMCID:PMC7307922)

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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 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.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Quon, Dr Tezz and Hudson, Dr Brian and Sergeev, Miss Eugenia and Milligan, Professor Graeme and Tobin, Andrew and Barki, Ms Natasja
Authors: Rexen Ulven, E., Quon, T., Sergeev, E., Barki, N., Brvar, M., Hudson, B. D., Dutta, P., Højgaard Hansen, A., Bielefeldt, L. Ø., Tobin, A. B., McKenzie, C. J., Milligan, G., and Ulven, T.
College/School:College of Medical Veterinary and Life Sciences > School of Molecular Biosciences
College of Medical Veterinary and Life Sciences > School of Life Sciences
Journal Name:Journal of Medicinal Chemistry
Publisher:American Chemical Society
ISSN (Online):1520-4804
Published Online:06 March 2020
Copyright Holders:Copyright © 2020 American Chemical Society
First Published:First published in Journal of Medicinal Chemistry 63(7): 3577-3595
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
190801Designer Receptor Exclusively Activated by Designer Drug' to define the role of short chain fatty acids in metabolic disease and inflammation (Fatty acid DREADD)Graeme MilliganBiotechnology and Biological Sciences Research Council (BBSRC)BB/L027887/1MCSB - Molecular Pharmacology