Synthesis and SAR Study of Carbamoyl Pyridone Bicycle Derivatives as Potent Inhibitors of Influenza Cap-dependent Endonuclease

  • J Med Chem. 2019 Sep 12;62(17):8101-8114. doi: 10.1021/acs.jmedchem.9b00861.
Masayoshi Miyagawa  1 ,  Toshiyuki Akiyama  1 ,  Yoshiyuki Taoda  1 ,  Kenji Takaya  1 ,  Chika Takahashi-Kageyama  1 ,  Kenji Tomita  1 ,  Kazuya Yasuo  1 ,  Kazunari Hattori  1 ,  Shinya Shano  1 ,  Ryu Yoshida  1 ,  Takao Shishido  1 ,  Tomokazu Yoshinaga  1 ,  Akihiko Sato  1 ,  Makoto Kawai  1
Affiliations
  • 1. Shionogi Pharmaceutical Research Center, Shionogi & Company, Limited , 1-1, Futabacho, 3-chome , Toyonaka 561-0825 , Japan.
PMID: 31386363 DOI: 10.1021/acs.jmedchem.9b00861
Abstract

The medicinal chemistry and structure-activity relationships (SAR) for a novel series of carbamoyl pyridone bicycle (CAB) compounds as influenza Cap-dependent Endonuclease (CEN) inhibitors are disclosed. Substituent effects were evaluated at the C (N)-1, N-3, and C-7 positions of the CAB ring system using a docking study. Submicromolar EC50 values were achieved in the cellular assay with C-7-unsubstituted CAB which possessed a benzhydryl group on either the C-1 or the N-1 position. An N-3 substituent was found to be critical for the plasma protein binding effect in vitro, and the CAB-N analogue 2v exhibited reasonable total clearance (CLtot). More importantly, compound 2v displayed significant efficacy in a mouse model infected with influenza viruses.

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