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
| Autor: | Kathy A. Aldern, Douglas D. Richman, Ganesh D. Kini, James R. Beadle, Michael F. Gardner, Karl Y. Hostetler, Kristine N. Wright |
|---|---|
| Rok vydání: | 1998 |
| Předmět: |
Glycerol
0301 basic medicine Foscarnet Human cytomegalovirus Magnetic Resonance Spectroscopy 030106 microbiology Administration Oral Biological Availability Cytomegalovirus Herpesvirus 1 Human Microbial Sensitivity Tests medicine.disease_cause Antiviral Agents 01 natural sciences Virus Mice Structure-Activity Relationship 03 medical and health sciences In vivo medicine Animals Humans Prodrugs Cells Cultured Molecular Structure Chemistry General Medicine Prodrug medicine.disease Virology In vitro 0104 chemical sciences 010404 medicinal & biomolecular chemistry Herpes simplex virus Foscarnet Sodium HIV-1 medicine.drug |
| Zdroj: | Antiviral Chemistry and Chemotherapy. 9:33-40 |
| ISSN: | 2040-2066 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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