| Literature DB >> 29029933 |
R Ian Storer1, Andy Pike2, Nigel A Swain3, Aristos J Alexandrou4, Bruce M Bechle5, David C Blakemore3, Alan D Brown3, Neil A Castle6, Matthew S Corbett5, Neil J Flanagan7, David Fengas8, M Scott Johnson6, Lyn H Jones9, Brian E Marron6, C Elizabeth Payne4, David Printzenhoff6, David J Rawson10, Colin R Rose5, Thomas Ryckmans10, Jianmin Sun5, Jonathan W Theile6, Rubben Torella3, Elaine Tseng11, Joseph S Warmus5.
Abstract
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.Entities:
Keywords: Acid isostere; Ion channel; Pain; Voltage-gated
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Year: 2017 PMID： 29029933 DOI： 10.1016/j.bmcl.2017.09.056
Source DB: PubMed Journal: Bioorg Med Chem Lett ISSN： 0960-894X Impact factor: 2.823