4-Amino- and 4-guanidino-4H-pyran-6-carboxamides 4 and 5 related to zanamivir (GG167) are a new class of inhibitors of influenza virus sialidases. Structure-activity studies reveal that, in general, secondary amides are weak inhibitors of both influenza A and B viral sialidases. However, tertiary amides, which contain one or more small alkyl groups, show much greater inhibitory activity, particularly against the influenza A virus enzyme. The sialidase inhibitory activities of these compounds correlate well with their in vitro antiviral efficacy, and several of the most potent analogues displayed useful antiviral activity in vivo when evaluated in a mouse model of influenza A virus infection. Carboxamides which were highly active sialidase inhibitors in vitro also showed good antiviral activity in the mouse efficacy model of influenza A infection when administered intranasally but displayed modest activity when delivered by the intraperitoneal route.

Two novel analogues of lysine have been prepared in high enantiomeric and diastereomeric purity. These unnatural α-amino acids possess modified aminoalkyl side chains incorporating a pyrrolidine nucleus as a cyclic constraint.

Analogues of 4-guanidino-Neu5Ac2en (GG167) have been prepared containing alternative amide and sulfonamide substituents at the 5-position. (4S,5R,6R)-4-guanidino-5-(2,2,2-trifluoroacetylamino)-6-(1R,2R,3-trihydroxypropyl)-5,6-dihydro-4H-pyran-2-carboxylic acid 5 and (4S,5R,6R)-4-guanidino-5-methanesulfonylamino-6-(1R,2R,3-trihydroxypropyl)-5,6-dihydro-4H-pyran-2-carboxylic acid 6 were the only analogues which approached the activity of GG167, showing potent inhibition of influenza virus sialidases and good antiviral activity in vitro.

Two constrained analogues of (S)-lysine have been prepared, suitably protected for solid phase peptide synthesis, in high optical and diastereomeric purity. The key step is the alkylation of the 6-oxopipecolate derivative (6) with iodoacetonitrile.

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The title compound 2b has been synthesised in 8 steps from 2-deoxy-D-glucose (2-DG). Key transformations were an aldolase reaction utilising 2-DG to form the 9 carbon sugar 3, and then introduction of the required unsaturation and a 4-amino substitutent in a one-pot process. The poor inhibitory activity of 2b demonstrates that the 5-acetamido substitutent in 2,3-didehydro-2,4-dideoxy-4-guanidinyl-N-acetylneuraminic acid (GG167) 1 is critical for sialidase binding.