INHIBITION OF INFLUENZA-VIRUS INFECTIONS IN MICE BY GS4104, AN ORALLYEFFECTIVE INFLUENZA-VIRUS NEURAMINIDASE INHIBITOR

The carbocyclic transition state sialic acid analog GS4071 mino-3-[1-e thylpropoxy]-1-cyclohexane-1-carboxylic acid), a potent influenza viru s neuraminidase inhibitor, was highly inhibitory to influenza A/NWS/33 (H1N1), A/Victoria/3/75 (H3N2), A/Shangdong/09/93 (H3N2) and B/Hong K ong/5/72 viruses in Madin Darby canine kidney (MDCK) cells. The 50% ef fective concentrations in these experiments ranged from 1.8 to 59.5 mu M, with no cytotoxicity evident at 1000 mu M, using inhibition of vir al cytopathic effect determined visually and by neutral red dye uptake . The ethyl ester prodrug of GS4071, GS4104, administered by oral gava ge (p.o.), had significant inhibitory effects on infections in mice in duced by these viruses. Antiviral effects were seen as prevention of d eath, increase in mean day to death, inhibition of decline of arterial oxygen saturation, lessened lung consolidation and inhibition of infe ctious virus recovered from the lungs. No toxicity was seen in dosages up to 100 mg/kg/day (highest evaluated). Comparison experiments run v ersus the influenza A (H1N1) virus-induced infection using GS4104, GS4 071 and the neuraminidase inhibitor zanamivir (GG167, 4-guanidino-Neu5 Ac2en), all administered p.o., indicated a 10-fold or greater potency for inhibiting the infection by GS4104. The minimum effective dosage f or GS4104 was 0.1 mg/kg/day, with the compound administered twice dail y for 5 days beginning 4 h pre-virus exposure. Oral therapy with GS410 4 could be delayed from 48 to at least 60 h after exposure of mice to influenza A (H1N1) virus and still render a significant antiviral effe ct, the time of delay being dependent on the viral challenge dose. Int ranasal instillation of GS4071 and GG167 to mice infected with influen za virus was highly inhibitory to the infection, the minimum effective dosages to significantly prevent death being 0.01 mg/kg/day for GS407 1 and 0.1 mg/kg/day for GG167. Caging of infected mice treated with 10 mg/kg/day of GS4104 with infected saline-treated animals did not tran sfer any influenza-inhibitory effect to the latter animals. These data provide strong evidence of the potential of orally administered GS410 4 for treatment of influenza A and B virus infections in humans. (C) 1 998 Elsevier Science B.V. All rights reserved.