Monocyclic L-nucleosides with type 1 cytokine-inducing activity

J Med Chem. 2000 Mar 9;43(5):1019-28. doi: 10.1021/jm9905514.

Abstract

A series of 1,2,4-triazole L-nucleosides were synthesized and evaluated for their ability to stimulate type 1 cytokine production by activated human T cells in direct comparison to the known active agent ribavirin. Among the compounds prepared, 1-beta-L-ribofuranosyl-1,2,4-triazole-3-carboxamide (5, ICN 17261) was found to be the most uniformly potent compound. Conversion of the 3-carboxamide group of 5 to a carboxamidine functionality resulted in 1-beta-L-ribofuranosyl-1,2,4-triazole-3-carboxamidine hydrochloride (10), which induced cytokine levels comparable to 5 for two of the three type 1 cytokines examined. Modification of the carbohydrate moiety of 5 provided compounds of reduced activity. Significantly, ICN 17261 offers interesting immunomodulatory potential for the treatment of diseases where type 1 cytokines play an important role.

MeSH terms

  • Adjuvants, Immunologic / chemical synthesis*
  • Adjuvants, Immunologic / chemistry
  • Adjuvants, Immunologic / pharmacology
  • Antiviral Agents / chemistry
  • Antiviral Agents / pharmacology
  • Cytokines / metabolism*
  • Enzyme-Linked Immunosorbent Assay
  • Humans
  • In Vitro Techniques
  • Interferon-gamma / metabolism
  • Interleukin-2 / metabolism
  • Nucleosides / chemical synthesis*
  • Nucleosides / chemistry
  • Nucleosides / pharmacology
  • Ribavirin / chemical synthesis*
  • Ribavirin / chemistry
  • Ribavirin / pharmacology
  • Stereoisomerism
  • Structure-Activity Relationship
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / metabolism
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Adjuvants, Immunologic
  • Antiviral Agents
  • Cytokines
  • Interleukin-2
  • Nucleosides
  • Tumor Necrosis Factor-alpha
  • Ribavirin
  • Interferon-gamma