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 <b>11a</b> was identified as a potent and metabolically stable influenza inhibitor. <b>11a</b> demonstrated a favorable oral pharmacokinetic profile and in vivo efficacy in mice. In addition, it was found that <b>11a</b> was not at risk of metabolism via aldehyde oxidase, an advantage over previously described inhibitors of this class. The crystal structure of <b>11a</b> bound to influenza A PB2 cap region is disclosed here and deposited to the PDB.