Dimeric zanamivir conjugates with various linking groups are potent, long-lasting inhibitors of influenza neuraminidase including H5N1 avian influenza.

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Macdonald SJ, Cameron R, Demaine DA, Fenton RJ, Foster G, Gower D, Hamblin JN, Hamilton S, Hart GJ, Hill AP, Inglis GG, Jin B, Jones HT, McConnell DB, McKimm-Breschkin J, Mills G, Nguyen V, Owens IJ, Parry N, Shanahan SE, Smith D, Watson KG, Wu WY, Tucker SP

Dimeric zanamivir conjugates with various linking groups are potent, long-lasting inhibitors of influenza neuraminidase including H5N1 avian influenza.

J Med Chem. 2005 Apr 21;48(8):2964-71.

PubMed ID

15828835 [ View in PubMed

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Abstract

The synthesis, antiviral and pharmacokinetic properties of zanamivir (ZMV) dimers 8 and 13 are described. The compounds are highly potent neuraminidase (NA) inhibitors which, along with dimer 3, are being investigated as potential second generation inhaled therapies both for the treatment of influenza and for prophylactic use. They show outstanding activity in a 1 week mouse influenza prophylaxis assay, and compared with ZMV, high concentrations of 8 and 13 are found in rat lung tissue after 1 week. Retention of compounds in rat lung tissue correlated both with molecular weight (excluding 3 and 15) and with a capacity factor K' derived from immobilized artificial membrane (IAM) chromatography (including 3 and 15). Pharmacokinetic parameters for 3, 8 and 13 in rats show the compounds have short to moderate plasma half-lives, low clearances and low volumes of distribution. Dimer 3 shows NA inhibitory activity against N1 viruses including the recent highly pathogenic H5N1 A/Chicken/Vietnam/8/2004. In plaque reduction assays, 3, 8 and 13 show good to outstanding potency against a panel of nine flu A and B virus strains. Consistent with its shorter and more rigid linking group, dimer 8 has been successfully crystallized.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Zanamivir	Neuraminidase	Protein	Influenza A virus (strain A/Bangkok/1/1979 H3N2)	Yes	Inhibitor	Details