In Vitro Pharmacokinetic Optimizations of AM2-S31N Channel Blockers Led to the Discovery of Slow-Binding Inhibitors with Potent Antiviral Activity against Drug-Resistant Influenza A Viruses

Influenza viruses are respiratory
pathogens that are responsible
for both seasonal influenza epidemics and occasional influenza pandemics.
The narrow therapeutic window of oseltamivir, coupled with the emergence
of drug resistance, calls for the next-generation of antivirals. With
our continuous interest in developing AM2-S31N inhibitors as oral
influenza antivirals, we report here the progress of optimizing the
in vitro pharmacokinetic (PK) properties of AM2-S31N inhibitors. Several
AM2-S31N inhibitors, including compound 10b, were discovered
to have potent channel blockage, single to submicromolar antiviral
activity, and favorable in vitro PK properties. The antiviral efficacy
of compound 10b was also synergistic with oseltamivir
carboxylate. Interestingly, binding kinetic studies (Kd, Kon, and Koff) revealed several AM2-S31N inhibitors that have similar Kd values but significantly different Kon and Koff values.
Overall, this study identified a potent lead compound (10b) with improved in vitro PK properties that is suitable for the in
vivo mouse model studies.