2,8-Diazaspiro[4.5]decan-8-yl)pyrimidin-4-amine potent CCR4 antagonists capable of inducing receptor endocytosis

Lena Shukla, Laura A. Ajram, Malcolm Begg, Brian Evans, Rebecca H. Graves, Simon T. Hodgson, Sean M. Lynn, Afjal H. Miah, Jonathan M. Percy, Panayiotis A. Procopiou, Stephen A. Richards, Robert J. Slack

Research output: Contribution to journalArticle

1 Citation (Scopus)

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 [125I]-TARC binding assay with a pKi of 8.8, and the [35S]-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.

LanguageEnglish
Pages14-25
Number of pages12
JournalEuropean Journal of Medicinal Chemistry
Volume115
Early online date27 Feb 2016
DOIs
Publication statusPublished - 10 Jun 2016

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Endocytosis
Amines
Assays
Allosteric Site
Chemokine Receptors
Cell Surface Receptors
Human Activities
Polymerization
Actins
Blood
Molecules

Keywords

  • CCR4 antagonist
  • Endocytosis
  • receptor internalisation

Cite this

Shukla, Lena ; Ajram, Laura A. ; Begg, Malcolm ; Evans, Brian ; Graves, Rebecca H. ; Hodgson, Simon T. ; Lynn, Sean M. ; Miah, Afjal H. ; Percy, Jonathan M. ; Procopiou, Panayiotis A. ; Richards, Stephen A. ; Slack, Robert J. / 2,8-Diazaspiro[4.5]decan-8-yl)pyrimidin-4-amine potent CCR4 antagonists capable of inducing receptor endocytosis. In: European Journal of Medicinal Chemistry. 2016 ; Vol. 115. pp. 14-25.
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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 [125I]-TARC binding assay with a pKi of 8.8, and the [35S]-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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Shukla, L, Ajram, LA, Begg, M, Evans, B, Graves, RH, Hodgson, ST, Lynn, SM, Miah, AH, Percy, JM, Procopiou, PA, Richards, SA & Slack, RJ 2016, '2,8-Diazaspiro[4.5]decan-8-yl)pyrimidin-4-amine potent CCR4 antagonists capable of inducing receptor endocytosis' European Journal of Medicinal Chemistry, vol. 115, pp. 14-25. https://doi.org/10.1016/j.ejmech.2016.02.058

2,8-Diazaspiro[4.5]decan-8-yl)pyrimidin-4-amine potent CCR4 antagonists capable of inducing receptor endocytosis. / Shukla, Lena; Ajram, Laura A.; Begg, Malcolm; Evans, Brian; Graves, Rebecca H.; Hodgson, Simon T.; Lynn, Sean M.; Miah, Afjal H.; Percy, Jonathan M.; Procopiou, Panayiotis A.; Richards, Stephen A.; Slack, Robert J.

In: European Journal of Medicinal Chemistry, Vol. 115, 10.06.2016, p. 14-25.

Research output: Contribution to journalArticle

TY - JOUR

T1 - 2,8-Diazaspiro[4.5]decan-8-yl)pyrimidin-4-amine potent CCR4 antagonists capable of inducing receptor endocytosis

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 - 2016/6/10

Y1 - 2016/6/10

N2 - 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 [125I]-TARC binding assay with a pKi of 8.8, and the [35S]-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.

AB - 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 [125I]-TARC binding assay with a pKi of 8.8, and the [35S]-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.

KW - CCR4 antagonist

KW - Endocytosis

KW - receptor internalisation

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U2 - 10.1016/j.ejmech.2016.02.058

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M3 - Article

VL - 115

SP - 14

EP - 25

JO - European Journal of Medicinal Chemistry

T2 - European Journal of Medicinal Chemistry

JF - European Journal of Medicinal Chemistry

SN - 0223-5234

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