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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 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.

SUBMITTER: McGowan DC

PROVIDER: S-EPMC7611167 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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

McGowan David C DC Balemans Wendy W Embrechts Werner W Motte Magali M Keown Jeremy R JR Buyck Christophe C Corbera Jordi J Funes Mario M Moreno Laura L Cooymans Ludwig L Tahri Abdellah A Eymard Julien J Stoops Bart B Strijbos Rudy R Van den Berg Joke J Fodor Ervin E Grimes Jonathan M JM Koul Anil A Jonckers Tim H M THM Raboisson Pierre P Guillemont Jérôme J

Journal of medicinal chemistry 20191030 21

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 11 ...[more]

PMID: 31647875

Dataset Information

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

Publications

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

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