Discovery and optimization of pyridazinone non-nucleoside inhibitors of HIV-1 reverse transcriptase

Bioorg Med Chem Lett. 2008 Aug 1;18(15):4352-4. doi: 10.1016/j.bmcl.2008.06.072. Epub 2008 Jun 28.

Abstract

A series of benzyl pyridazinones were evaluated as HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs). Several members of this series showed good activity against the wild-type virus and NNRTI-resistant viruses. The binding of inhibitor 5a to HIV-RT was analyzed by surface plasmon resonance spectroscopy. Pharmacokinetic studies of 5a in rat and dog demonstrated that this compound has good oral bioavailability in animal species. The crystal structure of a complex between HIV-RT and inhibitor 4c is also described.

MeSH terms

  • Animals
  • Dogs
  • Drug Resistance, Viral / drug effects
  • HIV Reverse Transcriptase / antagonists & inhibitors*
  • Inhibitory Concentration 50
  • Molecular Structure
  • Pyridazines* / chemical synthesis
  • Pyridazines* / chemistry
  • Pyridazines* / pharmacology
  • Rats
  • Reverse Transcriptase Inhibitors* / chemical synthesis
  • Reverse Transcriptase Inhibitors* / chemistry
  • Reverse Transcriptase Inhibitors* / pharmacology
  • Structure-Activity Relationship

Substances

  • Pyridazines
  • Reverse Transcriptase Inhibitors
  • reverse transcriptase, Human immunodeficiency virus 1
  • HIV Reverse Transcriptase