Design, Synthesis, and Biological Evaluation of Novel Indoles Targeting the Influenza PB2 Cap Binding Region

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.