Dimeric Zanamivir Conjugates with Various Linking Groups Are Potent, Long-Lasting Inhibitors of Influenza Neuraminidase Including H5N1 Avian Influenza

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.

CS-8958, a Prodrug of the New Neuraminidase Inhibitor R-125489, Shows Long-Acting Anti-Influenza Virus Activity

“…It has been reported that some dimers of zanamivir show dissociation constant (K d ) values that are 0.5 to 1.5 orders of magnitude greater than those for zanamivir for NA inhibition activity and suggested that the high antiviral activity of the zanamivir dimers is a result of their ability to cross-link and aggregate virus particles. The dimers also showed long-lasting protective activities in a mouse influenza virus infection model (14,15). CS-8958 itself did not show a strong inhibition of NA, but it is suggested that intranasally administered CS-8958 works as a long-acting NA inhibitor in a mouse influenza virus infection model.…”

Existing Influenza Antivirals: Their Mechanisms of Action and Potential in the Face of Avian Influenza

“…85,86 These compounds exhibited long -lasting antiviral activity due to extremely long resistance times in the lungs, thus allowing a once -weekly dosing regimen. This raises the prospect for a new type of anti -infl uenza drug that could be administered as a single dose in the treatment of infl uenza, or just once a week in the prevention of infection.…”

Recent advances in the discovery and synthesis of neuraminidase inhibitors

“…Most of these compounds are reported to possess significantly better activity than zanamivir (≥ 100-fold) and the compounds remained in the rat lung for a longer period of time. The better potency of the polymers and their ability to have a prolonged antiviral effect is probably because of their polarity, molecular weight, and the polymeric structure that leads to a multivalent binding effect via intervirion and interneuraminidase linkages [29].…”

“…The synthesis of a dimeric compound is represented in Figure 12 and is described in a patent [120] and a publication [29]. Compound 20, as shown in Figure 1, on esterification with acetyl chloride and methanol followed by reaction with N,N′-bis-tert-butoxycarbonylpyrazole carboxamidine (92) produced protected guanidine derivative 93, in which the C-8 and C-9 hydroxyls are protected as carbonates to produce compound 94.…”