Anti-human immunodeficiency virus type 1 activities and pharmacokinetics of novel 6-substituted acyclouridine derivatives

Antimicrob Agents Chemother. 1990 Dec;34(12):2358-63. doi: 10.1128/AAC.34.12.2358.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antiviral Agents / pharmacokinetics
  • Antiviral Agents / pharmacology*
  • Cells, Cultured
  • Chromatography, High Pressure Liquid
  • Cytopathogenic Effect, Viral / drug effects
  • Female
  • HIV-1 / drug effects*
  • HIV-1 / physiology
  • Humans
  • Lymphocytes / drug effects
  • Rats
  • Thymine / analogs & derivatives*
  • Thymine / pharmacokinetics
  • Thymine / pharmacology
  • Virus Replication / drug effects

Substances

  • Antiviral Agents
  • Thymine