Optimization of 4‑Aminopiperidines as Inhibitors of Influenza A Viral Entry That Are Synergistic with Oseltamivir

Vaccination is the
most prevalent prophylactic means for controlling
seasonal influenza infections. However, an effective vaccine usually
takes at least 6 months to develop for the circulating strains. Therefore,
new therapeutic options are needed for the acute treatment of influenza
infections to control this virus and prevent epidemics/pandemics from
developing. We have discovered fast-acting, orally bioavailable acylated
4-aminopiperidines with an effective mechanism of action targeting
viral hemagglutinin (HA). Our data show that these compounds are potent
entry inhibitors of influenza A viruses. We present docking studies
that suggest an HA binding site for these inhibitors on H5N1. Compound 16 displayed a significant decrease of viral titer when evaluated
in the infectious assays with influenza virus H1N1 (A/Puerto Rico/8/1934)
or H5N1 (A/Vietnam/1203/2004) strains and the oseltamivir-resistant
strain with the most common H274Y mutation. In addition, compound 16 showed significant synergistic activity with oseltamivir
in vitro.