Discovery of GPR183 Agonists Based on an Antagonist Scaffold

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Standard

Discovery of GPR183 Agonists Based on an Antagonist Scaffold. / Kjær, Viktoria M.S.; Ieremias, Loukas; Daugvilaite, Viktorija; Lückmann, Michael; Frimurer, Thomas M.; Ulven, Trond; Rosenkilde, Mette M.; Våbenø, Jon.

I: ChemMedChem, Bind 16, Nr. 17, 2021, s. 2623-2627.

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt

Harvard

Kjær, VMS, Ieremias, L, Daugvilaite, V, Lückmann, M, Frimurer, TM, Ulven, T, Rosenkilde, MM & Våbenø, J 2021, 'Discovery of GPR183 Agonists Based on an Antagonist Scaffold', ChemMedChem, bind 16, nr. 17, s. 2623-2627. https://doi.org/10.1002/cmdc.202100301

APA

Kjær, V. M. S., Ieremias, L., Daugvilaite, V., Lückmann, M., Frimurer, T. M., Ulven, T., Rosenkilde, M. M., & Våbenø, J. (2021). Discovery of GPR183 Agonists Based on an Antagonist Scaffold. ChemMedChem, 16(17), 2623-2627. https://doi.org/10.1002/cmdc.202100301

Vancouver

Kjær VMS, Ieremias L, Daugvilaite V, Lückmann M, Frimurer TM, Ulven T o.a. Discovery of GPR183 Agonists Based on an Antagonist Scaffold. ChemMedChem. 2021;16(17):2623-2627. https://doi.org/10.1002/cmdc.202100301

Author

Kjær, Viktoria M.S. ; Ieremias, Loukas ; Daugvilaite, Viktorija ; Lückmann, Michael ; Frimurer, Thomas M. ; Ulven, Trond ; Rosenkilde, Mette M. ; Våbenø, Jon. / Discovery of GPR183 Agonists Based on an Antagonist Scaffold. I: ChemMedChem. 2021 ; Bind 16, Nr. 17. s. 2623-2627.

Bibtex

@article{d05534c9dcf6482fbca6e6c9ff419fe9,

title = "Discovery of GPR183 Agonists Based on an Antagonist Scaffold",

abstract = "The G protein-coupled receptor GPR183/EBI2, which is activated by oxysterols, is a therapeutic target for inflammatory and metabolic diseases where both antagonists and agonists are of potential interest. Using the piperazine diamide core of the known GPR183 antagonist (E)-3-(4-bromophenyl)-1-(4-(4-methoxybenzoyl)piperazin-1-yl)prop-2-en-1-one (NIBR189) as starting point, we identified and sourced 79 structurally related compounds that were commercially available. In vitro screening of this compound collection using a Ca2+ mobilization assay resulted in the identification of 10 compounds with agonist properties. To enable establishment of initial structure-activity relationship trends, these were supplemented with five in-house compounds, two of which were also shown to be GPR183 agonists. Taken together, our findings suggest that the agonist activity of this compound series is dictated by the substitution pattern of one of the two distal phenyl rings, which functions as a molecular efficacy-switch.",

keywords = "agonists, antagonists, drug discovery, GPR183, receptors",

author = "Kj{\ae}r, {Viktoria M.S.} and Loukas Ieremias and Viktorija Daugvilaite and Michael L{\"u}ckmann and Frimurer, {Thomas M.} and Trond Ulven and Rosenkilde, {Mette M.} and Jon V{\aa}ben{\o}",

note = "Publisher Copyright: {\textcopyright} 2021 The Authors. ChemMedChem published by Wiley-VCH GmbH",

year = "2021",

doi = "10.1002/cmdc.202100301",

language = "English",

volume = "16",

pages = "2623--2627",

journal = "Farmaco",

issn = "1860-7179",

publisher = "Wiley - V C H Verlag GmbH & Co. KGaA",

number = "17",

}

RIS

TY - JOUR

T1 - Discovery of GPR183 Agonists Based on an Antagonist Scaffold

AU - Kjær, Viktoria M.S.

AU - Ieremias, Loukas

AU - Daugvilaite, Viktorija

AU - Lückmann, Michael

AU - Frimurer, Thomas M.

AU - Ulven, Trond

AU - Rosenkilde, Mette M.

AU - Våbenø, Jon

PY - 2021

Y1 - 2021

N2 - The G protein-coupled receptor GPR183/EBI2, which is activated by oxysterols, is a therapeutic target for inflammatory and metabolic diseases where both antagonists and agonists are of potential interest. Using the piperazine diamide core of the known GPR183 antagonist (E)-3-(4-bromophenyl)-1-(4-(4-methoxybenzoyl)piperazin-1-yl)prop-2-en-1-one (NIBR189) as starting point, we identified and sourced 79 structurally related compounds that were commercially available. In vitro screening of this compound collection using a Ca2+ mobilization assay resulted in the identification of 10 compounds with agonist properties. To enable establishment of initial structure-activity relationship trends, these were supplemented with five in-house compounds, two of which were also shown to be GPR183 agonists. Taken together, our findings suggest that the agonist activity of this compound series is dictated by the substitution pattern of one of the two distal phenyl rings, which functions as a molecular efficacy-switch.

AB - The G protein-coupled receptor GPR183/EBI2, which is activated by oxysterols, is a therapeutic target for inflammatory and metabolic diseases where both antagonists and agonists are of potential interest. Using the piperazine diamide core of the known GPR183 antagonist (E)-3-(4-bromophenyl)-1-(4-(4-methoxybenzoyl)piperazin-1-yl)prop-2-en-1-one (NIBR189) as starting point, we identified and sourced 79 structurally related compounds that were commercially available. In vitro screening of this compound collection using a Ca2+ mobilization assay resulted in the identification of 10 compounds with agonist properties. To enable establishment of initial structure-activity relationship trends, these were supplemented with five in-house compounds, two of which were also shown to be GPR183 agonists. Taken together, our findings suggest that the agonist activity of this compound series is dictated by the substitution pattern of one of the two distal phenyl rings, which functions as a molecular efficacy-switch.

KW - agonists

KW - antagonists

KW - drug discovery

KW - GPR183

KW - receptors

U2 - 10.1002/cmdc.202100301

DO - 10.1002/cmdc.202100301

M3 - Journal article

C2 - 34270165

AN - SCOPUS:85111685562

VL - 16

SP - 2623

EP - 2627

JO - Farmaco

JF - Farmaco

SN - 1860-7179

IS - 17

ER -

ID: 276333816