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

Eur J Med Chem. 2016 Jun 10:115:14-25. doi: 10.1016/j.ejmech.2016.02.058. Epub 2016 Feb 27.

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.

Keywords: CCR4 antagonist; Endocytosis; Receptor internalisation.

MeSH terms

  • Dose-Response Relationship, Drug
  • Endocytosis / drug effects*
  • Humans
  • Molecular Structure
  • Pyrimidines / chemical synthesis
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacology*
  • Receptors, CCR4 / antagonists & inhibitors*
  • Receptors, CCR4 / metabolism
  • Spiro Compounds / chemical synthesis
  • Spiro Compounds / chemistry
  • Spiro Compounds / pharmacology*
  • Structure-Activity Relationship

Substances

  • 2,8-diazaspiro(4.5)decan-8-yl)pyrimidin-4-amine
  • CCR4 protein, human
  • Pyrimidines
  • Receptors, CCR4
  • Spiro Compounds