Development of Oseltamivir Phosphonate Congeners as Anti-Influenza Agents

摘要

Oseltamivir phosphonic acid (tamiphosphor, >3a), its monoethyl ester (>3c), guanidino-tamiphosphor (>4a) and its monoethyl ester (>4c) are potent inhibitors of influenza neuraminidases. They inhibit the replication of influenza viruses, including the oseltamivir-resistant H275Y strain, at low nM to pM levels, and significantly protect mice from infection with lethal doses of influenza viruses when orally administered with 1 mg/kg or higher doses. These compounds are stable in simulated gastric fluid, liver microsomes and human blood, and are largely free from binding to plasma proteins. Pharmacokinetic properties of these inhibitors are thoroughly studied in dogs, rats and mice. The absolute oral bioavailability of these compounds was lower than 12%. No conversion of monoester >4c to phosphonic acid >4a was observed in rats after intravenous administration, but partial conversion of >4c was observed with oral administration. Advanced formulation may be investigated to develop these new anti-influenza agents for better therapeutic use.