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Design, synthesis, and biological evaluation of novel indoles targeting the influenza PB2 cap binding region
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(2019) Design, synthesis, and biological evaluation of novel indoles targeting the influenza PB2 cap binding region. Journal of Medicinal Chemistry, 62 (21). pp. 9680-9690. doi:10.1021/acs.jmedchem.9b01091 ISSN 0022-2623.
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Official URL: http://doi.org/10.1021/acs.jmedchem.9b01091
Abstract
In the search for novel influenza inhibitors we evaluated 7-fluoro-substituted indoles as bioisosteric replacements for the 7-azaindole scaffold of Pimodivir, a PB2 (polymerase basic protein 2) inhibitor currently in clinical development. Specifically, a 5,7-difluoroindole derivative 11a was identified as a potent and metabolically stable influenza inhibitor. 11a demonstrated a favorable oral pharmacokinetic profile and in vivo efficacy in mice. In addition, it was found that 11a was not at risk of metabolism via aldehyde oxidase, an advantage over previously described inhibitors of this class. The crystal structure of 11a bound to influenza A PB2 cap region is disclosed here and deposited to the PDB.
Item Type: | Journal Article | ||||
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Divisions: | Faculty of Science, Engineering and Medicine > Science > Life Sciences (2010- ) | ||||
Journal or Publication Title: | Journal of Medicinal Chemistry | ||||
Publisher: | American Chemical Society | ||||
ISSN: | 0022-2623 | ||||
Official Date: | 14 November 2019 | ||||
Dates: |
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Volume: | 62 | ||||
Number: | 21 | ||||
Page Range: | pp. 9680-9690 | ||||
DOI: | 10.1021/acs.jmedchem.9b01091 | ||||
Status: | Peer Reviewed | ||||
Publication Status: | Published | ||||
Access rights to Published version: | Restricted or Subscription Access |
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