Anti-human immunodeficiency virus type 1 activities and pharmacokinetics of novel 6-substituted acyclouridine derivatives.
The novel 6-substituted acyclouridine derivatives 1-[(2-hydroxyethoxy)methyl]-6-phenylthiothymine (HEPT), 1-[(2-hydroxyethoxy)methyl]-6-(3-methylphenylthio)thymine (HEPT-M), 6-cyclohexylthio-1-[(2-hydroxyethoxy) methyl]thymine (HEPT-H), and 1-[(2-hydroxyethoxy)methyl]-6-phenylthio-2- thiothymine (HEPT-S) have proved to be potent and selective inhibitors of human immunodeficiency virus type 1 (HIV-1) replication in a variety of cell systems, including peripheral blood lymphocytes. They are not inhibitory to the replication of HIV-2. HEPT-S emerged as the most active congener, with a 50% inhibitory concentration of 1.6 microM for HIV-1 (human T-cell lymphotropic virus type IIIB) in MT-4 cells. We also examined the pharmacokinetics of the compounds following oral administration to rats. The pharmacokinetic profile varied considerably from one compound to another. The highest concentration in plasma (7.4 micrograms/ml, or 22.8 microM) was achieved by HEPT-S within 30 min after administration of an oral dose of 20 mg/kg of body weight. HEPT-S can be considered a promising candidate for the treatment of HIV-1 infections.
Baba
M
M
Department of Bacteriology, Fukushima Medical College, Japan.
De Clercq
E
E
Iida
S
S
Tanaka
H
H
Nitta
I
I
Ubasawa
M
M
Takashima
H
H
Sekiya
K
K
Umezu
K
K
Nakashima
H
H
D000818:Animals; D000998:Antiviral Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D003588:Cytopathogenic Effect, Viral / Q000187:drug effects; D005260:Female; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D008214:Lymphocytes / Q000187:drug effects; D051381:Rats; D013941:Thymine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D014779:Virus Replication / Q000187:drug effects
D000998:Antiviral Agents; D013941:Thymine