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

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

Affiliation

  • 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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