title: Oral administration of a prodrug of the influenza virus neuraminidase inhibitor GS 4071 protects mice and ferrets against influenza infection.
abstract: We have recently described GS 4071, a carbocyclic transition-state analog inhibitor of the influenza virus neuraminidase, which has potent inhibitory activity comparable to that of 4-guanidino-Neu5Ac2en (GG167; zanamivir) when tested against influenza A virus replication and neuraminidase activity in vitro. We now report that GS 4071 is active against several strains of influenza A and B viruses in vitro and that oral GS 4104, an ethyl ester prodrug which is converted to GS 4071 in vivo, is active in the mouse and ferret models of influenza virus infection. Oral administration of 10 mg of GS 4104 per kg of body weight per day caused a 100-fold reduction in lung homogenate viral titers and enhanced survival in mice infected with influenza A or B viruses. In ferrets, a 25-mg/kg dose of GS 4104 given twice daily reduced peak viral titers in nasal washings and eliminated constitutional responses to influenza virus infection including fever, increased nasal signs (sneezing, nasal discharge, mouth breathing), and decreased activity. Consistent with our demonstration that the parent compound is highly specific for influenza virus neuraminidases, no significant drug-related toxicity was observed after the administration of oral dosages of GS 4104 of up to 800 mg/kg/day for 14 days in nonclinical toxicology studies with rats. These results indicate that GS 4104 is a novel, orally active antiviral agent with the potential to be used for the prophylaxis and treatment of influenza A and B virus infections.
authors.affiliation: Gilead Sciences, Inc., Foster City, California 94404, USA. dirk_mendel@gilead.com
authors.forename: D B
authors.initials: DB
authors.lastname: Mendel
authors.forename: C Y
authors.initials: CY
authors.lastname: Tai
authors.forename: P A
authors.initials: PA
authors.lastname: Escarpe
authors.forename: W
authors.initials: W
authors.lastname: Li
authors.forename: R W
authors.initials: RW
authors.lastname: Sidwell
authors.forename: J H
authors.initials: JH
authors.lastname: Huffman
authors.forename: C
authors.initials: C
authors.lastname: Sweet
authors.forename: K J
authors.initials: KJ
authors.lastname: Jakeman
authors.forename: J
authors.initials: J
authors.lastname: Merson
authors.forename: S A
authors.initials: SA
authors.lastname: Lacy
authors.forename: W
authors.initials: W
authors.lastname: Lew
authors.forename: M A
authors.initials: MA
authors.lastname: Williams
authors.forename: L
authors.initials: L
authors.lastname: Zhang
authors.forename: M S
authors.initials: MS
authors.lastname: Chen
authors.forename: N
authors.initials: N
authors.lastname: Bischofberger
authors.forename: C U
authors.initials: CU
authors.lastname: Kim
mesh_terms: D000081:Acetamides / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D000284:Administration, Oral; D000588:Amines / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D004195:Disease Models, Animal; D005260:Female; D005289:Ferrets; D006146:Guanidines; D009980:Influenza A virus / Q000187:drug effects* / Q000254:growth & development; D009981:Influenza B virus / Q000187:drug effects* / Q000254:growth & development; D051379:Mice; D008807:Mice, Inbred BALB C; D009439:Neuraminidase / Q000037:antagonists & inhibitors* / Q000187:drug effects; D009976:Orthomyxoviridae Infections / Q000517:prevention & control*; D053139:Oseltamivir; D011355:Prodrugs / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D011714:Pyrans; D051381:Rats; D017207:Rats, Sprague-Dawley; D012794:Sialic Acids / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology; D014779:Virus Replication / Q000187:drug effects; D053243:Zanamivir
chemical_list: D000081:Acetamides; D000588:Amines; D000998:Antiviral Agents; D006146:Guanidines; D011355:Prodrugs; D011714:Pyrans; D012794:Sialic Acids; D053139:Oseltamivir; D009439:Neuraminidase; D053243:Zanamivir