title: Identification of GS 4104 as an orally bioavailable prodrug of the influenza virus neuraminidase inhibitor GS 4071.
abstract: GS 4071 is a potent carbocyclic transition-state analog inhibitor of influenza virus neuraminidase with activity against both influenza A and B viruses in vitro. GS 4116, the guanidino analog of GS 4071, is a 10-fold more potent inhibitor of influenza virus replication in tissue culture than GS 4071. In this study we determined the oral bioavailabilities of GS 4071, GS 4116, and their respective ethyl ester prodrugs in rats. Both parent compounds and the prodrug of the guanidino analog exhibited poor oral bioavailability (2 to 4%) and low peak concentrations in plasma (Cmaxs; Cmax <0.06 microg/ml). In contrast, GS 4104, the ethyl ester prodrug of GS 4071, exhibited good oral bioavailability (35%) as GS 4071 and high Cmaxs of GS 4071 (Cmax = 0.47 microg/ml) which are 150 times the concentration necessary to inhibit influenza virus neuraminidase activity by 90%. The bioavailability of GS 4104 as GS 4071 was also determined in mice (30%), ferrets (11%), and dogs (73%). The plasma of all four species exhibited high, sustained concentrations of GS 4071 such that at 12 h postdosing the concentrations of GS 4071 in plasma exceeded those necessary to inhibit influenza virus neuraminidase activity by 90%. These results demonstrate that GS 4104 is an orally bioavailable prodrug of GS 4071 in animals and that it has the potential to be an oral agent for the prevention and treatment of influenza A and B virus infections in humans.
authors.affiliation: Gilead Sciences, Foster City, California 94404, USA.
authors.forename: W
authors.initials: W
authors.lastname: Li
authors.forename: P A
authors.initials: PA
authors.lastname: Escarpe
authors.forename: E J
authors.initials: EJ
authors.lastname: Eisenberg
authors.forename: K C
authors.initials: KC
authors.lastname: Cundy
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: W
authors.initials: W
authors.lastname: Lew
authors.forename: M
authors.initials: M
authors.lastname: Williams
authors.forename: L
authors.initials: L
authors.lastname: Zhang
authors.forename: C U
authors.initials: CU
authors.lastname: Kim
authors.forename: N
authors.initials: N
authors.lastname: Bischofberger
authors.forename: M S
authors.initials: MS
authors.lastname: Chen
authors.forename: D B
authors.initials: DB
authors.lastname: Mendel
mesh_terms: D000081:Acetamides / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D000284:Administration, Oral; D000588:Amines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D001682:Biological Availability; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005289:Ferrets; D006868:Hydrolysis; D051379:Mice; D009439:Neuraminidase / Q000037:antagonists & inhibitors / Q000187:drug effects*; D009975:Orthomyxoviridae / Q000187:drug effects*; D009976:Orthomyxoviridae Infections / Q000378:metabolism*; D053139:Oseltamivir; D011355:Prodrugs / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
chemical_list: D000081:Acetamides; D000588:Amines; D000998:Antiviral Agents; D011355:Prodrugs; D053139:Oseltamivir; D009439:Neuraminidase