Highly potent and selective NaV1.7 inhibitors for use as intravenous agents and chemical probes

[Display omitted] The discovery and selection of a highly potent and selective NaV1.7 inhibitor PF-06456384, designed specifically for intravenous infusion, is disclosed. Extensive in vitro pharmacology and ADME profiling followed by in vivo preclinical PK and efficacy model data are discussed. A pr...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2017-11, Vol.27 (21), p.4805-4811
Main Authors: Storer, R. Ian, Pike, Andy, Swain, Nigel A., Alexandrou, Aristos J., Bechle, Bruce M., Blakemore, David C., Brown, Alan D., Castle, Neil A., Corbett, Matthew S., Flanagan, Neil J., Fengas, David, Johnson, M. Scott, Jones, Lyn H., Marron, Brian E., Payne, C. Elizabeth, Printzenhoff, David, Rawson, David J., Rose, Colin R., Ryckmans, Thomas, Sun, Jianmin, Theile, Jonathan W., Torella, Rubben, Tseng, Elaine, Warmus, Joseph S.
Format: Article
Language:English
Subjects:
Acid isostere
Ion channel
Pain
Voltage-gated
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Summary:[Display omitted] The discovery and selection of a highly potent and selective NaV1.7 inhibitor PF-06456384, designed specifically for intravenous infusion, is disclosed. Extensive in vitro pharmacology and ADME profiling followed by in vivo preclinical PK and efficacy model data are discussed. A proposed protein–ligand binding mode for this compound is also provided to rationalise the high levels of potency and selectivity over inhibition of related sodium channels. To further support the proposed binding mode, potent conjugates are described which illustrate the potential for development of chemical probes to enable further target evaluation.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2017.09.056