title: 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.
abstract: In a previous study, we reported that 1-O-octadecyl-sn-glycero-3-foscarnet (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-1)-infected cells. To evaluate the effect of substituting a 1-S-alkyl thioether for a 1-O-alkyl ether, we synthesized a series of PFA conjugates of 1-S-alkyl-sn-thioglycerols with varied 1-S-alkyl chain lengths. To establish structure-activity relationships we measured the in vitro antiviral activity of liposomal formulations of the drugs in cells infected with HCMV, HSV-1 or HIV-1. The optimum 1-S-alkyl chain length in the series was 16 to 18 carbon atoms. We compared the antiviral activity of 16- and 18-carbon alkyl thioglycerol versus alkylglycerol prodrugs and did not observe any significant differences in their antiviral activities. The series' most active member, 1-S-octadecyl-sn-glycero-3-foscarnet (ODSG-PFA) 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 plasma levels of 14C after oral administration of radiolabelled compounds. The peak plasma level of 14C was sevenfold higher following administration of [14C]ODSG-PFA than following an equimolar dose of [14C]PFA. Area-under-the-curve was 23-fold greater for ODSG-PFA than for PFA. Like previously reported alkyloxyether-lipid PFA conjugates, alkylthioether conjugates provided enhanced antiviral activity and oral bioavailability. However, S-ether conjugates may be metabolized differently than O-ether conjugates. More detailed in vivo pharmacokinetic evaluation of the alkyl-thioether-PFA conjugates is required.
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla 92093-0676, USA.
authors.forename: J R
authors.initials: JR
authors.lastname: Beadle
authors.forename: G D
authors.initials: GD
authors.lastname: Kini
authors.forename: K A
authors.initials: KA
authors.lastname: Aldern
authors.forename: M F
authors.initials: MF
authors.lastname: Gardner
authors.forename: K N
authors.initials: KN
authors.lastname: Wright
authors.forename: D D
authors.initials: DD
authors.lastname: Richman
authors.forename: K Y
authors.initials: KY
authors.lastname: Hostetler
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001682:Biological Availability; D002478:Cells, Cultured; D003587:Cytomegalovirus / Q000187:drug effects*; D017245:Foscarnet / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D005990:Glycerol / Q000737:chemistry*; D015497:HIV-1 / Q000187:drug effects*; D018259:Herpesvirus 1, Human / Q000187:drug effects*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D011355:Prodrugs / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000998:Antiviral Agents; D011355:Prodrugs; D017245:Foscarnet; D005990:Glycerol