Open AccessDesign, Synthesis, and Biological Evaluation of Novel Indoles Targeting the Influenza PB2 Cap Binding Region
Author(s) -
David McGowan,
Wendy Balemans,
Werner Embrechts,
Magali Motte,
J.R. Keown,
Christophe Buyck,
Jordi Corbera,
Matías Funes,
Laura Moreno,
Ludwig P. Cooymans,
Abdellah Tahri,
Julien Eymard,
Bart Stoops,
R Strijbos,
Joke Van Den Berg,
Ervin Fodor,
Jonathan M. Grimes,
Anil Koul,
Jonckers Thm.,
Pierre Raboisson,
Jérôme Guillemont
Publication year - 2019
Publication title -
journal of medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.01
H-Index - 261
eISSN - 1520-4804
pISSN - 0022-2623
DOI - 10.1021/acs.jmedchem.9b01091
Subject(s) - chemistry , protein data bank (rcsb pdb) , in vivo , lead compound , pharmacokinetics , derivative (finance) , biochemistry , in vitro , pharmacology , stereochemistry , medicine , microbiology and biotechnology , economics , financial economics , biology
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.