Second-Generation Zanamivir

In the challenge to develop potent influenza virus sialidase inhibitors, a large amount of research has been dedicated to the manipulation of every position on 11 except C3. Structure-activity relationship (SAR) studies carried out on compounds derived from 11 before and during the development of zanamivir (reviewed in [101-103]) revealed structural requirements to conserve the main interactions between the substrate inhibitor and the active site of NA, particularly with regards to the carboxylate, C4-guanidino, and C5-acetamido moieties. 

To overcome the limits of oral bioavailability of zanamivir, the development of second-generation zanamivir was pointed toward improving its pharmacokinetic properties. In this context, the most encouraging results were obtained with the phos-phonate analogue of zanamivir, with modification of the C7-hydroxy group or with a replacement of the glycerol side chain that also improved oral bioavailability compared to the original inhibitor 13 (Fig. 17.10). 

FIGURE 17.10 Analogues of zanamivir with improved bioavailability (a) phosphonate 

2 Functionalization of the C7 Position of Zanamivir X-ray studies of influenza virus sialidase in complex with a-Neu5Ac [66] and zanamivir [91] showed that the C7-OH is not involved in any direct interaction in the active site of influenza virus NA, and only the C8- and C9-hydroxy groups are involved in the binding interactions. Based on this knowledge, different manipulations have been attempted at Cl, for example, by a simple substitution of the C7-hydroxy group or alkylation 

FIGURE 17.12 Interaction of oseltamivir carboxylate (20) with the influenza virus sialidase active site. 

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Further Developments on the Neu5Ac2en Template Second-Generation Zanamivir... 

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