2,8-Diazaspiro[4.5]decan-8-yl)pyrimidin-4-amine potent CCR4 antagonists capable of inducing receptor endocytosis
Lena Shukla
1
,
Laura A Ajram
2
,
Malcolm Begg
2
,
Brian Evans
1
,
Rebecca H Graves
3
,
Simon T. Hodgson
1
,
Sean M Lynn
4
,
Afjal H Miah
1
,
Jonathan M Percy
5
,
Panayiotis A. Procopiou
6
,
Stephen A Richards
4
,
Robert J. Slack
2
Publication type: Journal Article
Publication date: 2016-06-01
scimago Q1
wos Q1
SJR: 1.142
CiteScore: 11.3
Impact factor: 5.9
ISSN: 02235234, 17683254
PubMed ID:
26991939
Organic Chemistry
Drug Discovery
General Medicine
Pharmacology
Abstract
A number of potent 2,8-diazaspiro[4.5]decan-8-yl)pyrimidin-4-amine CCR4 antagonists binding to the extracellular allosteric site were synthesised. (R)-N-(2,4-Dichlorobenzyl)-2-(2-(pyrrolidin-2-ylmethyl)-2,8-diazaspiro[4.5]decan-8-yl)pyrimidin-4-amine (R)-(18a) has high affinity in both the [(125)I]-TARC binding assay with a pKi of 8.8, and the [(35)S]-GTPγS functional assay with a pIC50 of 8.1, and high activity in the human whole blood actin polymerisation assay (pA2 = 6.7). The most potent antagonists were also investigated for their ability to induce endocytosis of CCR4 and were found to internalise about 60% of the cell surface receptors, a property which is not commonly shared by small molecule antagonists of chemokine receptors.
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Total citations:
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Citations from 2025:
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Shukla L. et al. 2,8-Diazaspiro[4.5]decan-8-yl)pyrimidin-4-amine potent CCR4 antagonists capable of inducing receptor endocytosis // European Journal of Medicinal Chemistry. 2016. Vol. 115. pp. 14-25.
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Shukla L., Ajram L. A., Begg M., Evans B., Graves R. H., Hodgson S. T., Lynn S. M., Miah A. H., Percy J. M., Procopiou P. A., Richards S. A., Slack R. J. 2,8-Diazaspiro[4.5]decan-8-yl)pyrimidin-4-amine potent CCR4 antagonists capable of inducing receptor endocytosis // European Journal of Medicinal Chemistry. 2016. Vol. 115. pp. 14-25.
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TY - JOUR
DO - 10.1016/j.ejmech.2016.02.058
UR - https://doi.org/10.1016/j.ejmech.2016.02.058
TI - 2,8-Diazaspiro[4.5]decan-8-yl)pyrimidin-4-amine potent CCR4 antagonists capable of inducing receptor endocytosis
T2 - European Journal of Medicinal Chemistry
AU - Shukla, Lena
AU - Ajram, Laura A
AU - Begg, Malcolm
AU - Evans, Brian
AU - Graves, Rebecca H
AU - Hodgson, Simon T.
AU - Lynn, Sean M
AU - Miah, Afjal H
AU - Percy, Jonathan M
AU - Procopiou, Panayiotis A.
AU - Richards, Stephen A
AU - Slack, Robert J.
PY - 2016
DA - 2016/06/01
PB - Elsevier
SP - 14-25
VL - 115
PMID - 26991939
SN - 0223-5234
SN - 1768-3254
ER -
Cite this
BibTex (up to 50 authors)
Copy
@article{2016_Shukla,
author = {Lena Shukla and Laura A Ajram and Malcolm Begg and Brian Evans and Rebecca H Graves and Simon T. Hodgson and Sean M Lynn and Afjal H Miah and Jonathan M Percy and Panayiotis A. Procopiou and Stephen A Richards and Robert J. Slack},
title = {2,8-Diazaspiro[4.5]decan-8-yl)pyrimidin-4-amine potent CCR4 antagonists capable of inducing receptor endocytosis},
journal = {European Journal of Medicinal Chemistry},
year = {2016},
volume = {115},
publisher = {Elsevier},
month = {jun},
url = {https://doi.org/10.1016/j.ejmech.2016.02.058},
pages = {14--25},
doi = {10.1016/j.ejmech.2016.02.058}
}