Journal of Medicinal Chemistry p. 8101 - 8114 (2019)
Update date:2022-08-15
Topics: Synthesis Structure-Activity Relationship (SAR) Study Potent Inhibitors
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
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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