ALKYLTHIOGLYCEROL PRODRUGS OF FOSCARNET - SYNTHESIS, ORAL BIOAVAILABILITY AND STRUCTURE-ACTIVITY STUDIES IN HUMAN CYTOMEGALOVIRUS, HERPES-SIMPLEX VIRUS TYPE 1 AND HUMAN-IMMUNODEFICIENCY-VIRUS TYPE 1-INFECTED CELLS

In a previous study, we reported that 1-O-octadecyl-sn-glycero-3-fosca rnet (ODG-PFA) was 40 to 93 times more potent than free foscarnet (PFA ) in human cytomegalovirus (HCMV)-, herpes simplex virus type 1 (HSV-1 )- and human immunodeficiency virus type 1 (HIV-l)-infected cells. To evaluate the effect of substituting a 1-S-alkyl thioether for a 1-O-al kyl ether, we synthesized a series of PFA conjugates of 1-S-alkyl-sn-t hioglycerols with varied l-S-alkyl chain lengths. To establish structu re-activity relationships we measured the in vitro antiviral activity of liposomal formulations of the drugs in cells infected with HCMV, HS V-1 or HIV-1. The optimum l-S-alkyl chain length in the series was 16 to 18 carbon atoms. We compared the antiviral activity of 16- and 18-c arbon alkyl thioglycerol versus alkylglycerol prodrugs and did not obs erve any significant differences in their antiviral activities. The se ries' most active member, 1-S-octadecyl-sn-glycero-3-foscarnet (ODSG-P FA) was 56-, eight- and 45-fold more active than PFA in HCMV-, HSV-1- and HIV-1-infected cells in vitro. The oral absorption of PFA and 1-S- octadecyl-sn-thioglycero-3-PFA was compared in mice by measuring plasm a levels of C-14 after oral administration of radiolabelled compounds. The peak plasma level of C-14 was sevenfold higher following administ ration of [C-14]ODSG-PFA than following an equimolar dose of [C-14]PFA . Area-under-the-curve was 23-fold greater for ODSG-PFA than for PFA. Like previously reported alkyloxyether-lipid PFA conjugates, alkylthio ether conjugates provided enhanced antiviral activity and oral bioavai lability. However, S-ether conjugates may be metabolized differently t han O-ether conjugates. More detailed in vivo pharmacokinetic evaluati on of the alkyl-thioether-PFA conjugates is required.