Glycerol side chain

Despite the presence of the more lipophilic side-chain in 18, compared to the glycerol side-chain of 12, a pro-drug strategy was necessary to achieve sufficient oral bioavailabUity. Thus, the ethyl ester pro-drug form of 18, oseltamivir (GS 4104,... 

Importantly, there was a general marked selectivity for inhibition of influenza A over influenza B viral sialidases in the carboxamide series (e.g. as seen with 27) (Smith et al. 1996, 1998), determined from crystallographic and molecular modelling studies (Smith et al. 1996 Taylor et al. 1998) to be due to the relative abilities of each of the sialidases to absorb the structural changes required to accommodate the hydrophobic alkyl chains in the glycerol side-chain binding pocket. In influenza... 

Andrews DM, Cherry PC, Humber DC, Jones PS, Keeling SP, Martin PE, Shaw CD, Swanson S (1999) Synthesis and influenza virus siahdase inhibitory activity of analogues of 4-guanidino-Neu5Ac2en (Zanamivir) modified in the glycerol side-chain. Eur J Med Chem 34 563-574... 

A number of C-6 carboxamide analogues were prepared in which the stereo-chemically complex glycerol side-chain of Zanamivir or 4-amino-4-deoxy-Neu5Ac2en was replaced entirely by secondary or tertiary amides with the general structure of 94 or 95.95,96 These series of compounds were prepared from the C-6 carboxylate 92 (prepared by periodate oxidation of the glycerol side-chain of 91) by amide couling via the activated pentafluorophenyl ester 93 (Scheme 3). 

The combined effects of a carbocyclic scaffold and replacement of the glycerol side-chain with an amide group were also investigated.125 Neither GS4071-like... 

Z. Jia, K. Koike, T. Nikaido, and T. Ohmoto, Two novel triterpenoid pentasaccharides with an unusual glycosyl glycerol side chain from Ardisia crenata, Tetrahedron, 50 (1994) 11853-11864. 

FIG. 9.—Conformational model of anion of 14 showing the proposed hydrogen-bond network and favored conformation of the glycerol side chain. [Reproduced with permission from Fig. 1 of M. F. Czamiecki and E. R. Thornton, J. Am. Chem. Soc., 98 (1976) 1023-1025.]... 

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). 

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