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

Research output: Contribution to journal › Journal article › Research › peer-review

Standard

Structure-Activity Relationship Studies of Tetrahydroquinolone Free Fatty Acid Receptor 3 Modulators. / Ulven, Elisabeth Rexen; Quon, Tezz; Sergeev, Eugenia; Barki, Natasja; Brvar, Matjaz; Hudson, Brian D; Dutta, Palash; Hansen, Anders Højgaard; Bielefeldt, Line Ø; Tobin, Andrew B; McKenzie, Christine J; Milligan, Graeme; Ulven, Trond.

In: Journal of Medicinal Chemistry, Vol. 63, No. 7, 09.04.2020, p. 3577-3595.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Ulven, ER, Quon, T, Sergeev, E, Barki, N, Brvar, M, Hudson, BD, Dutta, P, Hansen, AH, Bielefeldt, LØ, Tobin, AB, McKenzie, CJ, Milligan, G & Ulven, T 2020, 'Structure-Activity Relationship Studies of Tetrahydroquinolone Free Fatty Acid Receptor 3 Modulators', Journal of Medicinal Chemistry, vol. 63, no. 7, pp. 3577-3595. https://doi.org/10.1021/acs.jmedchem.9b02036

APA

Ulven, E. R., Quon, T., Sergeev, E., Barki, N., Brvar, M., Hudson, B. D., Dutta, P., Hansen, A. H., Bielefeldt, L. Ø., Tobin, A. B., McKenzie, C. J., Milligan, G., & Ulven, T. (2020). Structure-Activity Relationship Studies of Tetrahydroquinolone Free Fatty Acid Receptor 3 Modulators. Journal of Medicinal Chemistry, 63(7), 3577-3595. https://doi.org/10.1021/acs.jmedchem.9b02036

Vancouver

Ulven ER, Quon T, Sergeev E, Barki N, Brvar M, Hudson BD et al. Structure-Activity Relationship Studies of Tetrahydroquinolone Free Fatty Acid Receptor 3 Modulators. Journal of Medicinal Chemistry. 2020 Apr 9;63(7):3577-3595. https://doi.org/10.1021/acs.jmedchem.9b02036

Author

Ulven, Elisabeth Rexen ; Quon, Tezz ; Sergeev, Eugenia ; Barki, Natasja ; Brvar, Matjaz ; Hudson, Brian D ; Dutta, Palash ; Hansen, Anders Højgaard ; Bielefeldt, Line Ø ; Tobin, Andrew B ; McKenzie, Christine J ; Milligan, Graeme ; Ulven, Trond. / Structure-Activity Relationship Studies of Tetrahydroquinolone Free Fatty Acid Receptor 3 Modulators. In: Journal of Medicinal Chemistry. 2020 ; Vol. 63, No. 7. pp. 3577-3595.

Bibtex

@article{9ea921673c6e430daef012392d879f73,
title = "Structure-Activity Relationship Studies of Tetrahydroquinolone Free Fatty Acid Receptor 3 Modulators",
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.",
author = "Ulven, {Elisabeth Rexen} and Tezz Quon and Eugenia Sergeev and Natasja Barki and Matjaz Brvar and Hudson, {Brian D} and Palash Dutta and Hansen, {Anders H{\o}jgaard} and Bielefeldt, {Line {\O}} and Tobin, {Andrew B} and McKenzie, {Christine J} and Graeme Milligan and Trond Ulven",
year = "2020",
month = apr,
day = "9",
doi = "10.1021/acs.jmedchem.9b02036",
language = "English",
volume = "63",
pages = "3577--3595",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "7",

}

RIS

TY - JOUR

T1 - Structure-Activity Relationship Studies of Tetrahydroquinolone Free Fatty Acid Receptor 3 Modulators

AU - Ulven, Elisabeth Rexen

AU - Quon, Tezz

AU - Sergeev, Eugenia

AU - Barki, Natasja

AU - Brvar, Matjaz

AU - Hudson, Brian D

AU - Dutta, Palash

AU - Hansen, Anders Højgaard

AU - Bielefeldt, Line Ø

AU - Tobin, Andrew B

AU - McKenzie, Christine J

AU - Milligan, Graeme

AU - Ulven, Trond

PY - 2020/4/9

Y1 - 2020/4/9

N2 - 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.

AB - 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.

U2 - 10.1021/acs.jmedchem.9b02036

DO - 10.1021/acs.jmedchem.9b02036

M3 - Journal article

C2 - 32141297

VL - 63

SP - 3577

EP - 3595

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 7

ER -

ID: 239670552