Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 62, Issue 21, Pages 9680-9690Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.9b01091
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Funding
- Medical Research Council [MR/R009945/1]
- Wellcome Investigator Award [200835/Z/16/Z]
- Wellcome Trust [200835/Z/16/Z] Funding Source: Wellcome Trust
- MRC [MR/R009945/1] Funding Source: UKRI
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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.
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