tetano
Editor, Senior Moderator
J Med Chem. 2019 Aug 6. doi: 10.1021/acs.jmedchem.9b00861. [Epub ahead of print]
[h=1]Synthesis and SAR Study of Carbamoyl Pyridone Bicycle Derivatives as Potent Inhibitors of Influenza Cap-dependent Endonuclease.[/h] Miyagawa M, Akiyama T, Taoda Y, Takaya K, Takahashi-Kageyama C, Tomita K, Yasuo K, Hattori K, Shano S, Yoshida R, Shishido T, Yoshinaga T, Sato A, Kawai M.
[h=3]Abstract[/h] 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 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 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, the compound 2v displayed significant efficacy in a mouse model infected with influenza viruses.
PMID: 31386363 DOI: 10.1021/acs.jmedchem.9b00861
[h=1]Synthesis and SAR Study of Carbamoyl Pyridone Bicycle Derivatives as Potent Inhibitors of Influenza Cap-dependent Endonuclease.[/h] Miyagawa M, Akiyama T, Taoda Y, Takaya K, Takahashi-Kageyama C, Tomita K, Yasuo K, Hattori K, Shano S, Yoshida R, Shishido T, Yoshinaga T, Sato A, Kawai M.
[h=3]Abstract[/h] 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 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 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, the compound 2v displayed significant efficacy in a mouse model infected with influenza viruses.
PMID: 31386363 DOI: 10.1021/acs.jmedchem.9b00861