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Design, synthesis, and biological evaluation of novel indoles targeting the influenza PB2 cap binding region

DOI: 10.1021/acs.jmedchem.9b01091 DOI Help

Authors: David Craig Mcgowan (Janssen Pharmaceutica) , Wendy Balemans (Janssen Pharmaceutica) , Werner Embrechts (Janssen Pharmaceutica) , Magali Motte (Janssen-Cilag) , Jeremy Keown (University of Oxford) , Christophe Buyck (Janssen Pharmaceutica) , Jordi Corbera (Eurofins Villapharma Research) , Mario Funes (Eurofins Villapharma Research) , Laura Moreno (Eurofins Villapharma Research) , Ludwig Cooymans (Janssen Pharmaceutica) , Abdellah Tahri (Janssen Pharmaceutica) , Julien Eymard (Novalix) , Bart Stoops (Janssen Pharmaceutica) , Rudy Strijbos (Charles River Labs Beerse) , Joke Van Den Berg (Janssen Pharmaceutica) , Ervin Fodor (University of Oxford) , Jonathan Grimes (University of Oxford; Diamond Light Source) , Anil Koul (Janssen Pharmaceutica) , Tim H. M. Jonckers (Janssen Pharmaceutica) , Pierre Raboisson (Janssen Pharmaceutica) , Jerome Guillemont (Janssen-Cilag)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Journal Of Medicinal Chemistry

State: Published (Approved)
Published: October 2019
Diamond Proposal Number(s): 14744

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.

Journal Keywords: Influenza; indole; bioisostere

Subject Areas: Biology and Bio-materials, Chemistry, Medicine


Instruments: I03-Macromolecular Crystallography

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