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Antimicrobial Agents and Chemotherapy, March 1998, p. 647-653, Vol. 42, No. 3
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Identification of GS 4104 as an Orally Bioavailable Prodrug of the Influenza Virus Neuraminidase Inhibitor GS 4071

Weixing Li,1 Paul A. Escarpe,1 Eugene J. Eisenberg,1 Kenneth C. Cundy,1 Clive Sweet,2 Kenneth J. Jakeman,2 James Merson,3 Willard Lew,1 Matt Williams,1 Lijun Zhang,1 Choung U. Kim,1 Norbert Bischofberger,1 Ming S. Chen,1 and Dirk B. Mendel1,*

Gilead Sciences, Foster City, California 94404,1 and School of Biological Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT,2 and Pfizer Central Research, Sandwich, Kent CT139 NJ,3 United Kingdom

Received 11 August 1997/Returned for modification 3 November 1997/Accepted 22 December 1997

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 µg/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 µg/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.

* Corresponding author. Mailing address: Gilead Sciences, Inc., 333 Lakeside Dr., Foster City, CA 94404. Phone: (650) 573-4839. Fax: (650) 573 4890. E-mail: dirk_mendel{at}gilead.com.

Antimicrobial Agents and Chemotherapy, March 1998, p. 647-653, Vol. 42, No. 3
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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