Key result
Compound 2v shows significant efficacy and reasonable clearance in an influenza mouse model.
Why the study?
The medicinal chemistry and SAR of carbamoyl pyridone bicycle compounds as influenza Cap-dependent endonuclease inhibitors were investigated to identify potent antiviral agents.
A novel series of carbamoyl pyridone bicycle compounds demonstrated potent influenza Cap-dependent endonuclease inhibition and in vivo efficacy in a mouse model.
May support preclinical advancement of this scaffold for influenza; leaves open human translation and safety.
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 EC 50 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 (CL tot ). More importantly, compound 2v displayed significant efficacy in a mouse model infected with influenza viruses.
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Miyagawa et al. (2019) studied Influenza. Carbamoyl pyridone bicycle (CAB) compounds (compound 2v) was evaluated on Efficacy in a mouse model infected with influenza viruses. Compound 2v, a carbamoyl pyridone bicycle derivative, displayed significant efficacy in a mouse model infected with influenza viruses and exhibited reasonable total clearance.
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