Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 115, Issue -, Pages 14-25Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2016.02.058
Keywords
CCR4 antagonist; Receptor internalisation; Endocytosis
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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 [I-125]-TARC binding assay with a pK(i) of 8.8, and the [S-35]-GTP gamma S functional assay with a pIC(50) of 8.1, and high activity in the human whole blood actin polymerisation assay (pA(2) = 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. (C) 2016 Elsevier Masson SAS. All rights reserved.
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