Click-Chemistry-Mediated Synthesis of Selective Melanocortin Receptor 4 Agonists

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Standard

Click-Chemistry-Mediated Synthesis of Selective Melanocortin Receptor 4 Agonists. / Palmer, Daniel; Gonçalves, Juliana P.L.; Hansen, Louise V.; Wu, Boqian; Hald, Helle; Schoffelen, Sanne; Diness, Frederik; Le Quement, Sebastian T.; Nielsen, Thomas E.; Meldal, Morten.

I: Journal of Medicinal Chemistry, Bind 60, Nr. 21, 2017, s. 8716-8730.

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt

Harvard

Palmer, D, Gonçalves, JPL, Hansen, LV, Wu, B, Hald, H, Schoffelen, S, Diness, F, Le Quement, ST, Nielsen, TE & Meldal, M 2017, 'Click-Chemistry-Mediated Synthesis of Selective Melanocortin Receptor 4 Agonists', Journal of Medicinal Chemistry, bind 60, nr. 21, s. 8716-8730. https://doi.org/10.1021/acs.jmedchem.7b00353

APA

Palmer, D., Gonçalves, J. P. L., Hansen, L. V., Wu, B., Hald, H., Schoffelen, S., Diness, F., Le Quement, S. T., Nielsen, T. E., & Meldal, M. (2017). Click-Chemistry-Mediated Synthesis of Selective Melanocortin Receptor 4 Agonists. Journal of Medicinal Chemistry, 60(21), 8716-8730. https://doi.org/10.1021/acs.jmedchem.7b00353

Vancouver

Palmer D, Gonçalves JPL, Hansen LV, Wu B, Hald H, Schoffelen S o.a. Click-Chemistry-Mediated Synthesis of Selective Melanocortin Receptor 4 Agonists. Journal of Medicinal Chemistry. 2017;60(21):8716-8730. https://doi.org/10.1021/acs.jmedchem.7b00353

Author

Palmer, Daniel ; Gonçalves, Juliana P.L. ; Hansen, Louise V. ; Wu, Boqian ; Hald, Helle ; Schoffelen, Sanne ; Diness, Frederik ; Le Quement, Sebastian T. ; Nielsen, Thomas E. ; Meldal, Morten. / Click-Chemistry-Mediated Synthesis of Selective Melanocortin Receptor 4 Agonists. I: Journal of Medicinal Chemistry. 2017 ; Bind 60, Nr. 21. s. 8716-8730.

Bibtex

@article{78285d91edbb4613a8fc24ff0e834380,
title = "Click-Chemistry-Mediated Synthesis of Selective Melanocortin Receptor 4 Agonists",
abstract = "The melanocortin receptor 4 (MC4R) subtype of the melanocortin receptor family is a target for therapeutics to ameliorate metabolic dysfunction. Endogenous MC4R agonists possess a critical pharmacophore (HFRW), and cyclization of peptide agonists often enhances potency. Thus, 17 cyclized peptides were synthesized by solid phase click chemistry to develop novel, potent, selective MC4R agonists. Using cAMP measurements and a transcriptional reporter assay, we observed that several constrained agonists generated by a cycloaddition reaction displayed high selectivity (223- to 467-fold) toward MC4R over MC3R and MC5R receptor subtypes without compromising agonist potency. Significant variation was also observed between the EC50 values for the two assays, with robust levels of reporter expression measured at lower concentrations than those effecting appreciable increases in cAMP levels for the majority of the compounds tested. Collectively, we characterized significant elements that modulate the activity of the core pharmacophore for MC4R and provide a rationale for careful assay selection for agonist screening.",
author = "Daniel Palmer and Gon{\c c}alves, {Juliana P.L.} and Hansen, {Louise V.} and Boqian Wu and Helle Hald and Sanne Schoffelen and Frederik Diness and {Le Quement}, {Sebastian T.} and Nielsen, {Thomas E.} and Morten Meldal",
year = "2017",
doi = "10.1021/acs.jmedchem.7b00353",
language = "English",
volume = "60",
pages = "8716--8730",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "21",

}

RIS

TY - JOUR

T1 - Click-Chemistry-Mediated Synthesis of Selective Melanocortin Receptor 4 Agonists

AU - Palmer, Daniel

AU - Gonçalves, Juliana P.L.

AU - Hansen, Louise V.

AU - Wu, Boqian

AU - Hald, Helle

AU - Schoffelen, Sanne

AU - Diness, Frederik

AU - Le Quement, Sebastian T.

AU - Nielsen, Thomas E.

AU - Meldal, Morten

PY - 2017

Y1 - 2017

N2 - The melanocortin receptor 4 (MC4R) subtype of the melanocortin receptor family is a target for therapeutics to ameliorate metabolic dysfunction. Endogenous MC4R agonists possess a critical pharmacophore (HFRW), and cyclization of peptide agonists often enhances potency. Thus, 17 cyclized peptides were synthesized by solid phase click chemistry to develop novel, potent, selective MC4R agonists. Using cAMP measurements and a transcriptional reporter assay, we observed that several constrained agonists generated by a cycloaddition reaction displayed high selectivity (223- to 467-fold) toward MC4R over MC3R and MC5R receptor subtypes without compromising agonist potency. Significant variation was also observed between the EC50 values for the two assays, with robust levels of reporter expression measured at lower concentrations than those effecting appreciable increases in cAMP levels for the majority of the compounds tested. Collectively, we characterized significant elements that modulate the activity of the core pharmacophore for MC4R and provide a rationale for careful assay selection for agonist screening.

AB - The melanocortin receptor 4 (MC4R) subtype of the melanocortin receptor family is a target for therapeutics to ameliorate metabolic dysfunction. Endogenous MC4R agonists possess a critical pharmacophore (HFRW), and cyclization of peptide agonists often enhances potency. Thus, 17 cyclized peptides were synthesized by solid phase click chemistry to develop novel, potent, selective MC4R agonists. Using cAMP measurements and a transcriptional reporter assay, we observed that several constrained agonists generated by a cycloaddition reaction displayed high selectivity (223- to 467-fold) toward MC4R over MC3R and MC5R receptor subtypes without compromising agonist potency. Significant variation was also observed between the EC50 values for the two assays, with robust levels of reporter expression measured at lower concentrations than those effecting appreciable increases in cAMP levels for the majority of the compounds tested. Collectively, we characterized significant elements that modulate the activity of the core pharmacophore for MC4R and provide a rationale for careful assay selection for agonist screening.

U2 - 10.1021/acs.jmedchem.7b00353

DO - 10.1021/acs.jmedchem.7b00353

M3 - Journal article

C2 - 28972753

AN - SCOPUS:85033369785

VL - 60

SP - 8716

EP - 8730

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 21

ER -

ID: 186187335