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

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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.

Original languageEnglish
Pages (from-to)14-25
Number of pages12
JournalEuropean Journal of Medicinal Chemistry
Volume115
Early online date27 Feb 2016
DOIs
Publication statusPublished - 10 Jun 2016

Keywords

  • CCR4 antagonist
  • Endocytosis
  • receptor internalisation

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