期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 62, 期 21, 页码 9680-9690出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.9b01091
关键词
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资金
- 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
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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