Steven J Charlton

Summary

Affiliation: Novartis Institutes for BioMedical Research

Publications

  1. pmc Elusive equilibrium: the challenge of interpreting receptor pharmacology using calcium assays
    Steven J Charlton
    Novartis Institutes for BioMedical Research, Horsham, UK
    Br J Pharmacol 161:1250-65. 2010
  2. pmc Agonist efficacy and receptor desensitization: from partial truths to a fuller picture
    Steven J Charlton
    Novartis Institutes for BioMedical Research, Horsham, UK
    Br J Pharmacol 158:165-8. 2009
  3. doi The Influence of receptor kinetics on the onset and duration of action and the therapeutic index of NVA237 and tiotropium
    David A Sykes
    Novartis Institutes for BioMedical Research, Wimblehurst Road, Horsham, West Sussex, RH12 5AB, United Kingdom
    J Pharmacol Exp Ther 343:520-8. 2012
  4. doi An investigation into the structure-activity relationships associated with the systematic modification of the β(2)-adrenoceptor agonist indacaterol
    David Beattie
    Novartis Institutes for BioMedical Research, Respiratory Diseases Area, Horsham, United Kingdom
    Bioorg Med Chem Lett 22:6280-5. 2012
  5. doi Exploring the mechanism of agonist efficacy: a relationship between efficacy and agonist dissociation rate at the muscarinic M3 receptor
    David A Sykes
    Novartis Institutes for BioMedical Sciences, Wimblehurst Road, Horsham, West Sussex, UK
    Mol Pharmacol 76:543-51. 2009
  6. doi A physical properties based approach for the exploration of a 4-hydroxybenzothiazolone series of beta2-adrenoceptor agonists as inhaled long-acting bronchodilators
    David Beattie
    Novartis Institutes for BioMedical Research, Respiratory Diseases Area, Horsham, United Kingdom
    Bioorg Med Chem Lett 20:5302-7. 2010
  7. doi Long Receptor Residence Time of C26 Contributes to Super Agonist Activity at the Human β2 Adrenoceptor
    Elizabeth M Rosethorne
    Novartis Institutes for BioMedical Research, Horsham, West Sussex, United Kingdom E M R, M E B, K G, D A S, A s, J D W, S J C Novartis Institutes for Biomedical Research, Basel, Switzerland E R, A T, R A F and School of Life Sciences, Queen s Medical Centre, University of Nottingham, Nottingham, United Kingdom E M R, K G, D A S, S J C
    Mol Pharmacol 89:467-75. 2016
  8. ncbi Miniaturized receptor binding assays: complications arising from ligand depletion
    Clare M Scaramellini Carter
    Novartis Institutes for BioMedical Research, West Sussex, UK
    J Biomol Screen 12:255-66. 2007
  9. pmc Slow receptor dissociation is not a key factor in the duration of action of inhaled long-acting β2-adrenoceptor agonists
    David A Sykes
    Novartis Institutes for BioMedical Research, West Sussex, UK
    Br J Pharmacol 165:2672-83. 2012
  10. doi Measuring receptor target coverage: a radioligand competition binding protocol for assessing the association and dissociation rates of unlabeled compounds
    David A Sykes
    Novartis Institutes for BioMedical Research, Horsham, West Sussex, United Kingdom
    Curr Protoc Pharmacol . 2010

Collaborators

  • Mark R Dowling
  • Alexandre Trifilieff
  • Brian Cox
  • Peter Gedeck
  • Florian Mullershausen
  • Stephen C McKeown
  • Neil J Press
  • Georges Vauquelin
  • Robin A Fairhurst
  • Gareth Williams
  • Bernard Faller
  • J R Fozard
  • Zhengjin Jiang
  • David A Sykes
  • Elizabeth M Rosethorne
  • David Beattie
  • Michelle E Bradley
  • Diana Janus
  • Michelle Bradley
  • Robert J Turner
  • David Farr
  • Roger J Taylor
  • Helen Oakman
  • Andrew Brearley
  • Christine Lewis
  • David Beer
  • Afrah Sattikar
  • Emilie Renard
  • Nicola Arnold
  • David W Porter
  • Juliet R Leighton-Davies
  • Darryl Jones
  • John Reilly
  • Andrew Tuffnell
  • Julia Hatto
  • David Sykes
  • Martin Gosling
  • Clive McCarthy
  • Joe Fullerton
  • Zarin Brown
  • Bernard M Cuenoud
  • Ian Bruce
  • Elke Wissler
  • Francois Baur
  • Bernard Cuenoud
  • Clare M Scaramellini Carter
  • Cliff Battram
  • Karolina Gherbi
  • John D Wright
  • Danilo Guerini
  • Lynne Jordan
  • Peter Hunt
  • Rachel Profit
  • Neil McGuiness
  • Lyndon Brown
  • Craig Stamp
  • Albrecht Glaenzel
  • Paul Oakley
  • Inês Rodrigues
  • Sarah Lewis
  • Nichola Smith
  • Janet Maas
  • Des O'Connor
  • Friedrich Schuerch
  • Mark Mercer
  • Darren M Riddy
  • Lindsay Fawcett
  • Toby C Kent
  • Juliet Leighton-Davies
  • David A Sandham
  • Katharine L Turner
  • Neil McGuinness
  • Colin Howes
  • Frederique Loeuillet-Ritzler
  • Thomas Keller
  • Daniel Wyss
  • Alan Steward
  • Hannah Woodward
  • Paul Kirkham
  • Simon Watson
  • Heinz Moser
  • Ryan West
  • James Neef
  • Lana Nanson
  • Koremu Meja
  • Handan He
  • Claire Hayden
  • Rowan Stringer
  • Sheila Garman
  • Gillian Spooner

Detail Information

Publications24

  1. pmc Elusive equilibrium: the challenge of interpreting receptor pharmacology using calcium assays
    Steven J Charlton
    Novartis Institutes for BioMedical Research, Horsham, UK
    Br J Pharmacol 161:1250-65. 2010
    ..Finally we end with a discussion on practical approaches to accurately estimate the affinity of insurmountable antagonists using calcium assays...
  2. pmc Agonist efficacy and receptor desensitization: from partial truths to a fuller picture
    Steven J Charlton
    Novartis Institutes for BioMedical Research, Horsham, UK
    Br J Pharmacol 158:165-8. 2009
    ..These findings challenge the notion that high-efficacy ligands always cause more functional desensitization...
  3. doi The Influence of receptor kinetics on the onset and duration of action and the therapeutic index of NVA237 and tiotropium
    David A Sykes
    Novartis Institutes for BioMedical Research, Wimblehurst Road, Horsham, West Sussex, RH12 5AB, United Kingdom
    J Pharmacol Exp Ther 343:520-8. 2012
    ....
  4. doi An investigation into the structure-activity relationships associated with the systematic modification of the β(2)-adrenoceptor agonist indacaterol
    David Beattie
    Novartis Institutes for BioMedical Research, Respiratory Diseases Area, Horsham, United Kingdom
    Bioorg Med Chem Lett 22:6280-5. 2012
    ....
  5. doi Exploring the mechanism of agonist efficacy: a relationship between efficacy and agonist dissociation rate at the muscarinic M3 receptor
    David A Sykes
    Novartis Institutes for BioMedical Sciences, Wimblehurst Road, Horsham, West Sussex, UK
    Mol Pharmacol 76:543-51. 2009
    ..These data suggest that kinetic models incorporating the mean lifetime of specific complexes will be required to fully explain the nature of agonist efficacy...
  6. doi A physical properties based approach for the exploration of a 4-hydroxybenzothiazolone series of beta2-adrenoceptor agonists as inhaled long-acting bronchodilators
    David Beattie
    Novartis Institutes for BioMedical Research, Respiratory Diseases Area, Horsham, United Kingdom
    Bioorg Med Chem Lett 20:5302-7. 2010
    ..This approach identified beta-phenethyl, alpha-substituted cyclopentyl and monoterpene N-substituents to be of particular interest for further evaluation, as exemplified by structures 19, 29 and 33, respectively...
  7. doi Long Receptor Residence Time of C26 Contributes to Super Agonist Activity at the Human β2 Adrenoceptor
    Elizabeth M Rosethorne
    Novartis Institutes for BioMedical Research, Horsham, West Sussex, United Kingdom E M R, M E B, K G, D A S, A s, J D W, S J C Novartis Institutes for Biomedical Research, Basel, Switzerland E R, A T, R A F and School of Life Sciences, Queen s Medical Centre, University of Nottingham, Nottingham, United Kingdom E M R, K G, D A S, S J C
    Mol Pharmacol 89:467-75. 2016
    ..This highlights the need to consider the temporal aspects of agonist binding and signaling when characterizing ligands as super agonists. ..
  8. ncbi Miniaturized receptor binding assays: complications arising from ligand depletion
    Clare M Scaramellini Carter
    Novartis Institutes for BioMedical Research, West Sussex, UK
    J Biomol Screen 12:255-66. 2007
    ..In addition to those previously described by others, the authors propose a simple method capable of correcting errors in competition binding experiments performed in conditions of ligand depletion...
  9. pmc Slow receptor dissociation is not a key factor in the duration of action of inhaled long-acting β2-adrenoceptor agonists
    David A Sykes
    Novartis Institutes for BioMedical Research, West Sussex, UK
    Br J Pharmacol 165:2672-83. 2012
    ..We have investigated whether the receptor binding kinetics of β(2) -adrenoceptor agonists can explain their observed onset of action and duration of effect in the clinic...
  10. doi Measuring receptor target coverage: a radioligand competition binding protocol for assessing the association and dissociation rates of unlabeled compounds
    David A Sykes
    Novartis Institutes for BioMedical Research, Horsham, West Sussex, United Kingdom
    Curr Protoc Pharmacol . 2010
    ..The protocol described in this unit is a kinetic radioligand competition binding assay that makes possible the determination of both the association and dissociation rates of unlabeled receptor ligands...
  11. doi The identification of 7-[(R)-2-((1S,2S)-2-benzyloxycyclopentylamino)-1-hydroxyethyl]-4-hydroxybenzothiazolone as an inhaled long-acting β2-adrenoceptor agonist
    Nicola Arnold
    Novartis Institutes for BioMedical Research, Respiratory Diseases Area, Horsham, United Kingdom Novartis Institutes for BioMedical Research, Respiratory Diseases Area, Basel, Switzerland
    Bioorg Med Chem Lett 24:4341-7. 2014
    ..On the basis of these data 2 was promoted as the backup development candidate to indacaterol from the Novartis LABA project. ..
  12. ncbi ATP priming of macrophage-derived chemokine responses in CHO cells expressing the CCR4 receptor
    Elizabeth M Rosethorne
    Novartis Horsham Research Centre, Wimblehurst Road, RH12 5AB, UK
    Naunyn Schmiedebergs Arch Pharmacol 370:64-70. 2004
    ..In conclusion, pre-stimulation of endogenous P2Y receptors with ATP facilitates Ca2+ signalling at the recombinant CCR4 receptor in CHO cells, although the mechanism by which this occurs remains to be defined...
  13. doi The in vitro metabolism of sphingosine-1-phosphate: identification; inhibition and pharmacological implications
    Michelle E Bradley
    Novartis Institutes for BioMedical Research, Wimblehurst Road, Horsham, West Sussex RH12 5AB, UK
    Eur J Pharmacol 672:56-61. 2011
    ..In the absence of sodium orthovanadate, it is envisaged that experiments involving exogenously applied S1P to broken cell preparations, whole cells or tissues, coupled with long incubation times will be subjected to metabolism...
  14. doi The discovery of potent, orally bioavailable pyrimidine-5-carbonitrile-6-alkyl CXCR2 receptor antagonists
    David W Porter
    Novartis Institutes for BioMedical Research, Horsham Research Centre, Wimblehurst Road, Horsham, West Sussex RH12 5AB, United Kingdom Electronic address
    Bioorg Med Chem Lett 24:3285-90. 2014
    ..The SAR was investigated by systematic variation of the aromatic group at c-6, the linker between c-2 and the halogenated ring, and the c-5 nitrile moiety. ..
  15. ncbi In vitro and in vivo pharmacological characterization of 5-[(R)-2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-one (indacaterol), a novel inhaled beta(2) adrenoceptor agonist with a 24-h duration of action
    Cliff Battram
    Novartis Institutes for BioMedical Research, Respiratory Diseases Area, Horsham, United Kingdom
    J Pharmacol Exp Ther 317:762-70. 2006
    ....
  16. doi Comparing the cardiovascular therapeutic indices of glycopyrronium and tiotropium in an integrated rat pharmacokinetic, pharmacodynamic and safety model
    Alexandre Trifilieff
    Respiratory Disease Area, Novartis Institutes for BioMedical Research, Wimblehurst Road, Horsham, West Sussex RH12 5AB, United Kingdom
    Toxicol Appl Pharmacol 287:9-16. 2015
    ..In our preclinical model there was an improved safety profile for glycopyrronium when compared with tiotropium. ..
  17. doi Efficacy is a contributing factor to the clinical onset of bronchodilation of inhaled beta(2)-adrenoceptor agonists
    Elizabeth M Rosethorne
    Novartis Institutes for BioMedical Research, Wimblehurst Road, Horsham, West Sussex, RH12 5AB, UK
    Naunyn Schmiedebergs Arch Pharmacol 382:255-63. 2010
    ..We have demonstrated that the rate of cAMP accumulation is influenced by agonist efficacy and that this, in combination with lipophilicity, may explain why beta(2) AR agonists demonstrate differences in their onset of action...
  18. doi Synthesis and evaluation of two series of 4'-aza-carbocyclic nucleosides as adenosine A2A receptor agonists
    David Beattie
    Novartis Institutes for BioMedical Research, Respiratory Diseases Area, Horsham, United Kingdom
    Bioorg Med Chem Lett 20:1219-24. 2010
    ..The propionamides 14-18 and the 4-hydroxymethylpyrazole 32 were determined to be the most potent and selective examples from the 4'-reversed amide and 4'-N-bonded heterocyclic series, respectively...
  19. pmc Investigating the molecular mechanisms through which FTY720-P causes persistent S1P1 receptor internalization
    David A Sykes
    Novartis Institutes for BioMedical Research, Horsham, West Sussex, UK
    Br J Pharmacol 171:4797-807. 2014
    ..We have investigated whether receptor binding kinetics and β-arrestin recruitment could play a role in the persistent internalization of the S1P1R by FTY720-P...
  20. doi Identification of novel IP receptor agonists using historical ligand biased chemical arrays
    Stephen C McKeown
    Novartis Institutes for BioMedical Research, Wimblehurst Road, Horsham, West Sussex RH12 5AB, UK Electronic address
    Bioorg Med Chem Lett 24:2247-50. 2014
    ..We rapidly identified multiple hits which were of suitable IP agonist potency. These relatively simple and strategically undecorated molecules present an ideal opportunity for optimization towards our target candidate profile. ..
  21. doi The identification of indacaterol as an ultralong-acting inhaled beta2-adrenoceptor agonist
    Francois Baur
    Respiratory Diseases Area, Novartis Institutes for BioMedical Research, Wimblehurst Road, Horsham, West Sussex RH12 5AB, UK
    J Med Chem 53:3675-84. 2010
    ..Further in vivo profiling of 1c supported the long duration of action and a wide therapeutic index following administration to the lung, which led to the compound being selected as a development candidate...
  22. doi Agonist-biased signaling at the histamine H4 receptor: JNJ7777120 recruits β-arrestin without activating G proteins
    Elizabeth M Rosethorne
    Novartis Institutes for BioMedical Research, Horsham, West Sussex, UK
    Mol Pharmacol 79:749-57. 2011
    ..In conclusion, we have demonstrated that JNJ7777120 recruits β-arrestin to the H(4) receptor, independent of G protein activation...
  23. pmc Quantifying the association and dissociation rates of unlabelled antagonists at the muscarinic M3 receptor
    Mark R Dowling
    Novartis Institutes for BioMedical Research, Wimblehurst Road, Horsham, West Sussex RH12 5AB
    Br J Pharmacol 148:927-37. 2006
    ....
  24. ncbi Assessing the minimum number of data points required for accurate IC50 determination
    Robert J Turner
    Novartis Institutes for BioMedical Research, Horsham, UK
    Assay Drug Dev Technol 3:525-31. 2005
    ..89). This study shows that it is possible to generate IC50 values from an appropriately designed primary inhibition screen using two compound concentrations, reducing the requirement for follow-up IC50 determinations...