Synthesis and Evaluation of 2-pyridinone Derivatives as HIV-1-specific Reverse Transcriptase Inhibitors. 2. Analogues of 3-aminopyridin-2(1H)-one

J Med Chem. 1992 Oct 16;35(21):3792-802. doi: 10.1021/jm00099a007.

Abstract

A series of nonnucleoside 3-aminopyridin-2(1H)-one derivatives was synthesized and evaluated for HIV-1 RT inhibitory properties. Several analogs proved to be potent and highly selective antagonists with in vitro IC50 values as low as 19 nM in the enzyme assay using rC.dG as template-primer. Two compounds from this series, 3-[[(4,7-dimethylbenzoxazol-2-yl)methyl]-amino]-5-ethyl-6-methy lpyridin-2(1H)-one (34, L-697,639) and the corresponding 4,7-dichloro analogue (37, L-697,661) inhibited the spread of HIV-1 IIIb infection by 95% in MT4 cell culture at concentrations of 25-50 nM and were selected for clinical trials as antiviral agents.

MeSH terms

  • Aminopyridines / chemistry
  • Aminopyridines / pharmacology*
  • Antiviral Agents / chemical synthesis
  • Antiviral Agents / pharmacology*
  • Benzoxazoles / chemical synthesis
  • Benzoxazoles / pharmacology*
  • Cells, Cultured
  • HIV Reverse Transcriptase
  • HIV-1 / drug effects*
  • HIV-1 / enzymology
  • Pyridones / chemical synthesis
  • Pyridones / chemistry
  • Pyridones / pharmacology*
  • Reverse Transcriptase Inhibitors*
  • Structure-Activity Relationship

Substances

  • Aminopyridines
  • Antiviral Agents
  • Benzoxazoles
  • Pyridones
  • Reverse Transcriptase Inhibitors
  • L 697639
  • L 697661
  • HIV Reverse Transcriptase