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

doi: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

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

^*Corresponding author for this work

Pure And Applied Chemistry

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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 pK_i 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.

Original language	English
Pages (from-to)	14-25
Number of pages	12
Journal	European Journal of Medicinal Chemistry
Volume	115
Early online date	27 Feb 2016
DOIs	https://doi.org/10.1016/j.ejmech.2016.02.058
Publication status	Published - 10 Jun 2016

Keywords

CCR4 antagonist
Endocytosis
receptor internalisation

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10.1016/j.ejmech.2016.02.058

Shukla-etal-EJMC2016-2,8-Diazaspiro[4.5]decan-8-yl)pyrimidin-4-amine-potent-CCR4Accepted author manuscript, 971 KBLicence: CC BY-NC-ND 4.0
EJMC910Accepted author manuscript, 496 KBLicence: CC BY-NC-ND 4.0

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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. (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, 115, 14-25. https://doi.org/10.1016/j.ejmech.2016.02.058

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

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.",

keywords = "CCR4 antagonist, Endocytosis, receptor internalisation",

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

year = "2016",

month = jun,

day = "10",

doi = "10.1016/j.ejmech.2016.02.058",

language = "English",

volume = "115",

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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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UR - http://www.sciencedirect.com/science/article/pii/S0223523416301489

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DO - 10.1016/j.ejmech.2016.02.058

M3 - Article

AN - SCOPUS:84960940457

SN - 0223-5234

VL - 115

SP - 14

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JO - European Journal of Medicinal Chemistry

JF - European Journal of Medicinal Chemistry

ER -

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

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