gs-4071 and 1-hydroxy-2-naphthoic-acid

Zanamivir (ZA) is a potent anti-influenza drug, but it cannot be administrated orally because of the hydrophilic carboxylate and guanidinium groups. Guanidino-oseltamivir (GO) is another effective neuraminidase inhibitor with polar guanidinium group under physiological conditions. The ester prodrugs ZA-HNAP (5) and GO-HNAP (6) were prepared to incorporate a 1-hydroxy-2-naphthoic (HNAP) moiety to attain good lipophilicity in the intramolecular ion-pairing forms. ZA-HNAP resumed high anti-influenza activity (EC(50)=48 nM), in cell-based anti-influenza assays, by releasing zanamivir along with nontoxic HNAP. Under similar conditions, the hydrolysis of the GO-HNAP ester was too sluggish to show the desired anti-influenza activity.

Topics: Administration, Oral; Antiviral Agents; Carbon Dioxide; Cell Line; Drug Evaluation, Preclinical; Enzyme Inhibitors; Esters; Guanidine; Humans; Hydrophobic and Hydrophilic Interactions; Influenza A virus; Influenza, Human; Ions; Molecular Structure; Naphthols; Neuraminidase; Oseltamivir; Prodrugs; Zanamivir