Publications by authors named "Nicholas P Barton"

4 Publications

  • Page 1 of 1

Distinct conformations of the chemokine receptor CCR4 with implications for its targeting in allergy.

J Immunol 2014 Apr 21;192(7):3419-27. Epub 2014 Feb 21.

Leukocyte Biology Section, Medical Research Council-Asthma UK Centre in Allergic Mechanisms of Asthma, National Heart and Lung Institute Division, Faculty of Medicine, Imperial College London, London SW7 2AZ, United Kingdom;

CC chemokine receptor 4 (CCR4) is expressed by Th2 and regulatory T cells and directs their migration along gradients of the chemokines CCL17 and CCL22. Both chemokines and receptor are upregulated in allergic disease, making CCR4 a therapeutic target for the treatment of allergy. We set out to assess the mechanisms underlying a previous report that CCL22 is a dominant ligand of CCR4, which may have implications for its therapeutic targeting. Human T cells expressing endogenous CCR4 and transfectants engineered to express CCR4 were assessed for receptor function, using assays of calcium release, chemotaxis, receptor endocytosis, and ligand binding. Despite the two ligands having equal potency in calcium flux and chemotaxis assays, CCL22 showed dominance in both receptor endocytosis assays and heterologous competitive binding assays. Using two different CCR4-specific Abs, we showed that CCR4 exists in at least two distinct conformations, which are differentially activated by ligand. A major population is activated by both CCL17 and CCL22, whereas a minor population is activated only by CCL22. Mutation of a single C-terminal residue K310 within a putative CCR4 antagonist binding site ablated activation of CCR4 by CCL17, but not by CCL22, despite having no effect on the binding of either ligand. We conclude that CCL17 and CCL22 are conformationally selective ligands of CCR4 and interact with the receptor by substantially different mechanisms. This finding suggests that the selective blockade of CCR4 in allergy may be feasible when one CCR4 ligand dominates, allowing the inhibition of Th2 signaling via one ligand while sparing regulatory T cell recruitment via another.
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http://dx.doi.org/10.4049/jimmunol.1300232DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3965571PMC
April 2014

Synthesis and structure-activity relationships of indazole arylsulfonamides as allosteric CC-chemokine receptor 4 (CCR4) antagonists.

J Med Chem 2013 Mar 27;56(5):1946-60. Epub 2013 Feb 27.

Department of Medicinal Chemistry, GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, United Kingdom.

A series of indazole arylsulfonamides were synthesized and examined as human CCR4 antagonists. Methoxy- or hydroxyl-containing groups were the more potent indazole C4 substituents. Only small groups were tolerated at C5, C6, or C7, with the C6 analogues being preferred. The most potent N3-substituent was 5-chlorothiophene-2-sulfonamide. N1 meta-substituted benzyl groups possessing an α-amino-3-[(methylamino)acyl]-group were the most potent N1-substituents. Strongly basic amino groups had low oral absorption in vivo. Less basic analogues, such as morpholines, had good oral absorption; however, they also had high clearance. The most potent compound with high absorption in two species was analogue 6 (GSK2239633A), which was selected for further development. Aryl sulfonamide antagonists bind to CCR4 at an intracellular allosteric site denoted site II. X-ray diffraction studies on two indazole sulfonamide fragments suggested the presence of an important intramolecular interaction in the active conformation.
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http://dx.doi.org/10.1021/jm301572hDOI Listing
March 2013

Discovery and optimization of highly ligand-efficient oxytocin receptor antagonists using structure-based drug design.

Bioorg Med Chem Lett 2009 Feb 24;19(3):990-4. Epub 2008 Nov 24.

GlaxoSmithKline Pharmaceuticals, New Frontiers Science Park (North), Coldharbour Road, Harlow, Essex CM19 5AD, England, United Kingdom.

A novel oxytocin antagonist was identified by 'scaffold-hopping' using Cresset FieldScreen molecular field similarity searching. A single cycle of optimization driven by an understanding of the key pharmacophoric elements required for activity led to the discovery of a potent, selective and highly ligand-efficient oxytocin receptor antagonist. Selectivity over vasopressin receptors was rationalized based on differences in the structure of the natural ligands.
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http://dx.doi.org/10.1016/j.bmcl.2008.11.064DOI Listing
February 2009

Discovery and optimisation of a potent and selective tertiary sulfonamide oxytocin antagonist.

Bioorg Med Chem Lett 2009 Jan 12;19(2):528-32. Epub 2008 Nov 12.

GlaxoSmithKline Pharmaceuticals, New Frontiers Science Park (North), Coldharbour Road, Harlow, Essex CM19 5AD, England, UK.

The optimisation of a tertiary sulfonamide high-throughput screening hit is described. A combination of high-throughput chemistry, pharmacophore analysis and in silico PK profiling resulted in the discovery of potent sulfonamide oxytocin receptor antagonists with oral exposure and good selectivity over vasopressin receptors.
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http://dx.doi.org/10.1016/j.bmcl.2008.11.018DOI Listing
January 2009