Zanamivir mimetics

Of all the influenza virus sialidase inhibitors based on zanamivir reported to date, the most promising compounds are those which contain a carbocyc-lic ring in place of the dihydropyran ring. Early work in this regard involved the use of Diels-Alder chemistry to ultimately provide access to the side- 

The carbocyclic zanamivir mimetic (53) inhibits influenza virus sialidase (IC50 = 1 x 10 9 M) with equal potency to zanamivir [120]. X-Ray crystallographic information derived from (53) bound to influenza sialidase shows that the compound binds in a similar orientation to that observed with zanamivir. However, the lipophilic 3-pentyl ether residue in (53), which sits in the same region as the glycerol side-chain of zanamivir, shows hydrophobic interactions with Glu-276, Ala-246, Arg-224 and Ile-222 [120]. The carboxy-late of Glu-276, which interacts with the C-8 and C-9 hydroxyls of zanamivir [53], is oriented away from the binding pocket when (53) is bound [120]. 

An alternative approach to the synthesis of compounds which mimic the sialosyl cation transition state intermediate (4) centres on jV-functionalised piperidines like (54) [125]. It is proposed that, upon protonation, the structure (54) would be electronically equivalent to that of resonance contributor (55) of the transition state intermediate (4) which bears the positive charge on the anomeric carbon. Whilst no information is given regarding the activity of compounds such as (54) against influenza sialidase [125], modest inhibition of bacterial sialidases is reported. It remains to be seen what effect, if any, the incorporation of some form of glycerol side-chain in this new struc- 

Influenza virus replication in human respiratory epithelial cells is efficiently inhibited by zanamivir. Little, if any, cytotoxicity has been reported 

A number of human trials have been conducted with zanamivir [98, 130] and the results from these studies strongly suggest that the drug is useful in both the prophylaxis and treatment of human influenza infection. Whilst the poor oral bioavailability of zanamivir may be considered an issue by some, the nature of influenza infection is such that delivery of the drug directly to the site of infection, via inhalation as a dry powder, may hold advantages. 

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The carbocyclic zanamivir mimetic GS4104, the ethyl ester of (53), entered phase II/III clinical studies towards the end of 1997. Although the detailed results from the clinical trials with this compound remain to be published, it appears [124] that it is also useful in the prophylaxis and treatment of experimentally infected patients. 

A convenient chemoenzymatic access to sialic acid mimetics as important inhibitors of influenza sialidases has been established by Nelson et al. (Fig. 35b) [191, 192]. Application of a pyruvate-dependent sialic acid aldolase improved by directed evolution disclosed a new route to the core structure of important pharmaceuticals, such as zanamivir (Relenza ). 

Oseltamivir (GS 4104, 4a), developed by Gilead/Hoffmann-LaRoche and marketed as Tamiflu , is the first commercially available orally active, noncarbohydrate mimetic of Zanamivir (3) [49-51]. It is based on a cyclohexene framework with a lipophilic moiety replacing the glycerol side chain of Zanamivir (3). It is orally administered as an ethyl ester prodrug GS 4104 (4a), which—upon absorption in the gastrointestinal tract—undergoes rapid enzymatic conversion by the action of... 

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