Design and synthesis of pyridone inhibitors of non-nucleoside reverse transcriptase

Bioorg Med Chem Lett. 2011 Dec 15;21(24):7344-50. doi: 10.1016/j.bmcl.2011.10.027. Epub 2011 Oct 17.

Abstract

Next generation NNRTIs are sought which possess both broad spectrum antiviral activity against key mutant strains and a high genetic barrier to the selection of new mutant viral strains. Pyridones were evaluated as an acyclic conformational constraint to replace the aryl ether core of MK-4965 (1) and the more rigid indazole constraint of MK-6186 (2). The resulting pyridone compounds are potent inhibitors of HIV RT and have antiviral activity in cell culture that is superior to other next generation NNRTI's.

MeSH terms

  • Binding Sites
  • Cell Line
  • Computer Simulation
  • Drug Design
  • Enzyme Activation / drug effects
  • HIV / enzymology
  • HIV Reverse Transcriptase / antagonists & inhibitors*
  • HIV Reverse Transcriptase / metabolism
  • Humans
  • Protein Structure, Tertiary
  • Pyrazoles / chemistry
  • Pyridines / chemistry
  • Pyridones / chemical synthesis
  • Pyridones / chemistry*
  • Pyridones / pharmacology
  • Reverse Transcriptase Inhibitors / chemical synthesis*
  • Reverse Transcriptase Inhibitors / chemistry
  • Reverse Transcriptase Inhibitors / pharmacology

Substances

  • 3-(5-((6-amino-1H-pyrazolo(3,4-b)pyridine-3-yl)methoxy)-2-chlorophenoxy)-5-chlorobenzonitrile
  • Pyrazoles
  • Pyridines
  • Pyridones
  • Reverse Transcriptase Inhibitors
  • HIV Reverse Transcriptase