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

作者：David C. McGowan, Wendy Balemans, Werner Embrechts, Magali Motte, J.R. Keown, Christophe Buyck, Jordi Corbera, Mario Funes, Laura Moreno, Ludwig Cooymans, Abdellah Tahri, Julien Eymard, Bart Stoops, Rudy Strijbos, Joke Van Den Berg, Ervin Fodor, Jonathan M. Grimes, Anil Koul, Tim H. M. Jonckers, Pierre Raboisson, Jérôme Guillemont · 发表于：Journal of Medicinal Chemistry · 年份：2019 · DOI：10.1021/acs.jmedchem.9b01091 · 被引用次数：31 · 研究领域：Influenza Virus Research Studies、RNA and protein synthesis mechanisms、Click Chemistry and Applications

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.