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

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...

Full description

Saved in:
Bibliographic Details
Published in:Journal of medicinal chemistry 2019-09, Vol.62 (17), p.8101-8114
Main Authors: Miyagawa, Masayoshi, Akiyama, Toshiyuki, Taoda, Yoshiyuki, Takaya, Kenji, Takahashi-Kageyama, Chika, Tomita, Kenji, Yasuo, Kazuya, Hattori, Kazunari, Shano, Shinya, Yoshida, Ryu, Shishido, Takao, Yoshinaga, Tomokazu, Sato, Akihiko, Kawai, Makoto
Format: Article
Language:English
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.9b00861