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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Abstract
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 |
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Status: | Published |
Refereed: | Yes |
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: | 0022-2623 |
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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