The Experts below are selected from a list of 24 Experts worldwide ranked by ideXlab platform

Antonio Mete - One of the best experts on this subject based on the ideXlab platform.

  • discovery of azd 2098 and azd 1678 two potent and bioavailable CCR4 Receptor antagonists
    ACS Medicinal Chemistry Letters, 2017
    Co-Authors: Nicholas Kindon, Glen Andrews, Andrew Baxter, David Cheshire, Paul Hemsley, Timothy Johnson, Yuzhen Liu, Dermot F Mcginnity, Mark Mchale, Antonio Mete
    Abstract:

    N-(5-Bromo-3-methoxypyrazin-2-yl)-5-chlorothiophene-2-sulfonamide 1 was identified as a hit in a CCR4 Receptor antagonist high-throughput screen (HTS) of a subset of the AstraZeneca compound bank. As a hit with a lead-like profile, it was an excellent starting point for a CCR4 Receptor antagonist program and enabled the rapid progression through the Lead Identification and Lead Optimization phases resulting in the discovery of two bioavailable CCR4 Receptor antagonist candidate drugs.

Steven J Charlton - One of the best experts on this subject based on the ideXlab platform.

  • atp priming of macrophage derived chemokine responses in cho cells expressing the CCR4 Receptor
    Naunyn-schmiedebergs Archives of Pharmacology, 2004
    Co-Authors: Elizabeth M Rosethorne, Juliet Leightondavies, David Beer, Steven J Charlton
    Abstract:

    The mechanism by which ATP primes for subsequent macrophage-derived chemokine (MDC) mediated intracellular calcium (Ca2+ i) responses at the human CCR4 Receptor stably expressed in Chinese hamster ovary (CHO) cells was investigated. MDC alone was unable to elicit a Ca2+ i response, but pre-stimulation of cells with ATP enabled a subsequent MDC-mediated Ca2+ i response with a pEC50 of 8.66±0.16. The maximal response elicited by MDC was dependent upon the concentration of ATP used to prime, but the pEC50 was stable at all ATP concentrations tested. Pertussis toxin pre-treatment did not effect the ATP response, but abolished that to MDC, demonstrating that priming with ATP did not alter G protein-coupling specificity of the CCR4 Receptor. Ionomycin and thapsigargin both increased Ca2+ i concentrations (pEC50s of 7.59±0.57 and 6.81±0.31 respectively), but were unable to prime for MDC responses, suggesting the priming mechanism was not dependent upon increases in Ca2+ i concentrations. Priming of the MDC response was still observed when experiments were performed with low Ca2+ e (70 μM), indicating that Ca2+ influx was not required for ATP to prime the CCR4 Receptor. Neither Ro31–8220 nor wortmannin affected priming, suggesting that protein kinase C and phosphoinositol 3-kinase were not involved. 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.

Nicholas Kindon - One of the best experts on this subject based on the ideXlab platform.

  • discovery of azd 2098 and azd 1678 two potent and bioavailable CCR4 Receptor antagonists
    ACS Medicinal Chemistry Letters, 2017
    Co-Authors: Nicholas Kindon, Glen Andrews, Andrew Baxter, David Cheshire, Paul Hemsley, Timothy Johnson, Yuzhen Liu, Dermot F Mcginnity, Mark Mchale, Antonio Mete
    Abstract:

    N-(5-Bromo-3-methoxypyrazin-2-yl)-5-chlorothiophene-2-sulfonamide 1 was identified as a hit in a CCR4 Receptor antagonist high-throughput screen (HTS) of a subset of the AstraZeneca compound bank. As a hit with a lead-like profile, it was an excellent starting point for a CCR4 Receptor antagonist program and enabled the rapid progression through the Lead Identification and Lead Optimization phases resulting in the discovery of two bioavailable CCR4 Receptor antagonist candidate drugs.

Elizabeth M Rosethorne - One of the best experts on this subject based on the ideXlab platform.

  • atp priming of macrophage derived chemokine responses in cho cells expressing the CCR4 Receptor
    Naunyn-schmiedebergs Archives of Pharmacology, 2004
    Co-Authors: Elizabeth M Rosethorne, Juliet Leightondavies, David Beer, Steven J Charlton
    Abstract:

    The mechanism by which ATP primes for subsequent macrophage-derived chemokine (MDC) mediated intracellular calcium (Ca2+ i) responses at the human CCR4 Receptor stably expressed in Chinese hamster ovary (CHO) cells was investigated. MDC alone was unable to elicit a Ca2+ i response, but pre-stimulation of cells with ATP enabled a subsequent MDC-mediated Ca2+ i response with a pEC50 of 8.66±0.16. The maximal response elicited by MDC was dependent upon the concentration of ATP used to prime, but the pEC50 was stable at all ATP concentrations tested. Pertussis toxin pre-treatment did not effect the ATP response, but abolished that to MDC, demonstrating that priming with ATP did not alter G protein-coupling specificity of the CCR4 Receptor. Ionomycin and thapsigargin both increased Ca2+ i concentrations (pEC50s of 7.59±0.57 and 6.81±0.31 respectively), but were unable to prime for MDC responses, suggesting the priming mechanism was not dependent upon increases in Ca2+ i concentrations. Priming of the MDC response was still observed when experiments were performed with low Ca2+ e (70 μM), indicating that Ca2+ influx was not required for ATP to prime the CCR4 Receptor. Neither Ro31–8220 nor wortmannin affected priming, suggesting that protein kinase C and phosphoinositol 3-kinase were not involved. 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.

David Chantry - One of the best experts on this subject based on the ideXlab platform.

  • synthesis of spirolactams and spiropiperidines as CCR4 Receptor antagonists
    Tetrahedron Letters, 2006
    Co-Authors: Joshua D Hansen, Brad Newhouse, Shelley Allen, Aaron S Anderson, Todd C Eary, Justin G Schiro, John J Gaudino, Ellen R Laird, Andrew Allen, David Chantry
    Abstract:

    The synthesis of racemic and non-racemic spirocyclic lactams that display high binding affinity toward CCR4 is described. Two distinct series of spirocycles were prepared from the common intermediate 9.

  • Divergent Effects of Interleukin-4 and Interferon-γ on Macrophage-Derived Chemokine Production: An Amplification Circuit of Polarized T Helper 2 Responses
    Blood, 1998
    Co-Authors: Raffaella Bonecchi, David Chantry, Silvano Sozzani, Giovanna D'amico, Paola Allavena, Johnny T. Stine, Walter Luini, Alberto Mantovani
    Abstract:

    Macrophage-derived chemokine (MDC) is a CC chemokine that recognizes the CCR4 Receptor and is selective for T helper 2 (Th2) versus T helper 1 (Th1) cells. The present study was designed to investigate the effect of the prototypic Th2/Th1 cytokines, interleukin-4 (IL-4) and interferon-gamma (IFN-gamma), on the production of MDC by human monocytes. IL-4 and IL-13 caused a time-dependent (plateau at 24 hours) and concentration-dependent (EC50 2 and 10 ng/mL, respectively) increase of MDC mRNA levels in monocytes. Increased expression of MDC mRNA was associated with protein release in the supernatant. MDC expression and production induced by IL-4 and IL-13 were inhibited by IFN-gamma. IFN-gamma also suppressed the constitutive expression of MDC in mature macrophages and dendritic cells. These results delineate an amplification loop of polarized Th2 responses based on differential regulation of MDC production by IL-4 and IL-13 versus IFN-gamma and on the selectivity of this chemokine for polarized Th2 cells.