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 [(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.
authors.affiliation: Department of Medicinal Chemistry, Respiratory TAU, GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, United Kingdom.
authors.forename: Lena
authors.initials: L
authors.lastname: Shukla
authors.affiliation: Department of Respiratory Biology, Respiratory TAU, GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, United Kingdom.
authors.forename: Laura A
authors.initials: LA
authors.lastname: Ajram
authors.affiliation: Department of Respiratory Biology, Respiratory TAU, GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, United Kingdom.
authors.forename: Malcolm
authors.initials: M
authors.lastname: Begg
authors.affiliation: Department of Medicinal Chemistry, Respiratory TAU, GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, United Kingdom.
authors.forename: Brian
authors.initials: B
authors.lastname: Evans
authors.affiliation: Department of Drug Metabolism and Pharmacokinetics, Respiratory TAU, GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, United Kingdom.
authors.forename: Rebecca H
authors.initials: RH
authors.lastname: Graves
authors.affiliation: Department of Medicinal Chemistry, Respiratory TAU, GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, United Kingdom.
authors.forename: Simon T
authors.initials: ST
authors.lastname: Hodgson
authors.affiliation: UK Analytical Chemistry, Platform Technology & Science, GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, United Kingdom.
authors.forename: Sean M
authors.initials: SM
authors.lastname: Lynn
authors.affiliation: Department of Medicinal Chemistry, Respiratory TAU, GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, United Kingdom.
authors.forename: Afjal H
authors.initials: AH
authors.lastname: Miah
authors.affiliation: WestCHEM Department of Pure and Applied Chemistry, University of Strathclyde, 295 Cathedral Street, Glasgow, G1 1XL, United Kingdom.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Percy
authors.affiliation: Department of Medicinal Chemistry, Respiratory TAU, GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, United Kingdom. Electronic address: pan.a.procopiou@gsk.com.
authors.forename: Panayiotis A
authors.initials: PA
authors.lastname: Procopiou
authors.affiliation: UK Analytical Chemistry, Platform Technology & Science, GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, United Kingdom.
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Richards
authors.affiliation: Department of Respiratory Biology, Respiratory TAU, GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, United Kingdom.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Slack
mesh_terms: D004305:Dose-Response Relationship, Drug; D004705:Endocytosis / Q000187:drug effects*; D006801:Humans; D015394:Molecular Structure; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D054398:Receptors, CCR4 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013141:Spiro Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: C000612729:2,8-diazaspiro(4.5)decan-8-yl)pyrimidin-4-amine; C515354:CCR4 protein, human; D011743:Pyrimidines; D054398:Receptors, CCR4; D013141:Spiro Compounds
keywords: CCR4 antagonist; Endocytosis; Receptor internalisation