Journal article
Design, synthesis, and biological evaluation of novel indoles targeting the influenza PB2 cap binding region
- 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.
- Publication status:
- Published
- Peer review status:
- Peer reviewed
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- Files:
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(Preview, Accepted manuscript, 852.9KB, Terms of use)
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- Publisher copy:
- 10.1021/acs.jmedchem.9b01091
Authors
- Publisher:
- American Chemical Society
- Journal:
- Journal of medicinal chemistry More from this journal
- Volume:
- 62
- Issue:
- 21
- Pages:
- 9680-9690
- Place of publication:
- United States
- Publication date:
- 2019-10-24
- DOI:
- EISSN:
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1520-4804
- ISSN:
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0022-2623
- Pmid:
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31647875
- Language:
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English
- Pubs id:
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1068983
- Local pid:
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pubs:1068983
- Deposit date:
-
2020-01-28
Terms of use
- Copyright holder:
- American Chemical Society
- Copyright date:
- 2019
- Rights statement:
- © 2019 American Chemical Society
- Notes:
- This is the accepted manuscript version of the article. The final version is available from American Chemical Society at: https://doi.org/10.1021/acs.jmedchem.9b01091
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