Biaryl ethers as potent allosteric inhibitors of reverse transcriptase and its key mutant viruses: aryl substituted pyrazole as a surrogate for the pyrazolopyridine motif

Bioorg Med Chem Lett. 2010 Aug 1;20(15):4328-32. doi: 10.1016/j.bmcl.2010.06.083. Epub 2010 Jun 17.

Abstract

Biaryl ethers were recently reported as potent NNRTIs. Herein, we disclose a detailed effort to modify the previously reported compound 1. We have designed and synthesized a series of novel pyrazole derivatives as a surrogate for pyrazolopyridine motif that were potent inhibitors of HIV-1 RT with nanomolar intrinsic activity on the WT and key mutant enzymes and potent antiviral activity in infected cells.

MeSH terms

  • Allosteric Regulation
  • Animals
  • Anti-HIV Agents / chemical synthesis
  • Anti-HIV Agents / chemistry*
  • Anti-HIV Agents / pharmacokinetics
  • Dogs
  • Ethers / chemical synthesis
  • Ethers / chemistry*
  • Ethers / pharmacokinetics
  • HIV Reverse Transcriptase / antagonists & inhibitors*
  • HIV Reverse Transcriptase / genetics
  • HIV Reverse Transcriptase / metabolism
  • Humans
  • Mutation
  • Pyrazoles / chemical synthesis
  • Pyrazoles / chemistry*
  • Pyrazoles / pharmacokinetics
  • Pyridines / chemical synthesis
  • Pyridines / chemistry*
  • Pyridines / pharmacokinetics
  • Rats
  • Reverse Transcriptase Inhibitors / chemical synthesis
  • Reverse Transcriptase Inhibitors / chemistry*
  • Reverse Transcriptase Inhibitors / pharmacokinetics
  • Structure-Activity Relationship

Substances

  • Anti-HIV Agents
  • Ethers
  • Pyrazoles
  • Pyridines
  • Reverse Transcriptase Inhibitors
  • pyrazolopyridine
  • reverse transcriptase, Human immunodeficiency virus 1
  • HIV Reverse Transcriptase