Sialidase Inhibitors Based on Five-Membered Ring Scaffolds

4 Sialidase Inhibitors Based on Five-Membered Ring Scaffolds 

A number of researchers have reported and demonstrated that maintaining the appropriate position of the substituents on a cyclic scaffold to interact with the established conserved amino acid residues involved in substrate binding can lead to development of new classes of influenza virus sialidase inhibitors [117]. Two drugs based on five-membered ring scaffolds have been developed as potent sialidase inhibitors. Cyclopentane derivative 24 (BCX-1812, peramivir) [117, 118] and pyrrolidine derivative 25 (ABT-675) [119] show nanomolar levels of inhibition of both influenza A and B viral sialidases (Fig. 17.13). 

An X-ray crystal structure of peramivir (24) in complex with influenza A N9 showed interactions of the 3-pentyl group with S4 and S5 [117]. Due to the different stereochemistry of the guanidino moiety of 24 compared to zanamivir, a water molecule was displaced from S2 when 24 was bound. The different binding mode of the guanidine moiety within the active site provided the reason by which 24 showed inhibitory activity also for zanamivir-resistant influenza virus sialidase strains [117,120], Compound 24, which showed comparable or better efficacy in vivo than zanamivir and oseltamivir [121, 122], successfully completed animal studies and is in phase III clinical trials. 

Another remarkable influenza virus sialidase inhibitor, derivative 25 [119], was developed based on a pyrrolidine core by Abbott Laboratories [119, 123], X-ray crystal studies surprisingly observed hydrophobic interactions of the d.s-propenyl group within S2, which is normally involved in charge-charge interaction as with the guanidino moiety in zanamivir [69], The side-chain methyl and methoxy groups of 

FIGURE 17.13 Sialidase inhibitors with five-membered rings. 

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