Glycerol side chain modification

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). 

The discovery, in the early 1990s, that zanamivir was a potent and selective inhibitor of influenza virus sialidase prompted several researchers to investigate the synthesis of Neu5Ac2en based analogues of zanamivir. Much of this effort was a consequence of the fact that zanamivir (12) must be administered as a nasal spray, due to its poor oral bioavailability and rapid excretion [101,102], and the desire to identify new sialidase inhibitors with modified physicochemical properties. Several researchers have described structure-activity relationship studies based on zanamivir (vide infra), with most modifications reported at C-4, C-5, and the glycerol side-chain. 

An attempt to increase the metabolic stabihty of sialosides like 161, for example against mammahan sialidases, led to the corresponding non-carbohydrate mimic 179 (Fig. 6) [83]. Based on manual docking of 161 to a homology model of MAG (Fig. 7a, b), beneficial modifications of side chains in the 2-, 5-, and 9-position of Neu5Ac [28, 72, 73, 81] combined with the replacement of the pyranose core by a cyclohexane ring, the substitution of the 4-OH by an acetamide, and the simplification of the glycerol side chain in the 6-position led to 179 (Fig. 6). 

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