Targeting delavirdine/atevirdine resistant HIV-1: identification of (alkylamino)piperidine-containing bis(heteroaryl)piperazines as broad spectrum HIV-1 reverse transcriptase inhibitors

J Med Chem. 1996 Sep 13;39(19):3769-89. doi: 10.1021/jm960158n.

Abstract

A novel class of bis(heteroaryl)piperazine (BHAP) analogs which possesses the ability to inhibit NNRTI (non-nucleoside reverse transcriptase inhibitor) resistant recombinant HIV-1 reverse transcriptase (RT) and NNRTI resistant variants of HIV-1 has been identified via targeted screening. Further investigation of the structure-activity relationships of close congeners of these novel (alkylamino)piperidine BHAPs (AAP-BHAPs) led to the synthesis of several compounds possessing the desired phenotype (e.g., activity against recombinant RTs carrying the Y181C and P236L substitutions). Further structural modifications were required to inhibit metabolism and modulate solubility in order to obtain compounds with the desired biological profile as well as appropriate pharmaceutical properties. The AAP-BHAPs with the most suitable characteristics were compounds 7, 15, and 36.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Anti-HIV Agents / chemical synthesis*
  • Anti-HIV Agents / pharmacokinetics
  • Anti-HIV Agents / pharmacology
  • Biological Availability
  • Cell Line
  • Delavirdine
  • Drug Resistance, Microbial*
  • Drug Stability
  • HIV Reverse Transcriptase
  • HIV-1 / drug effects*
  • Indoles / pharmacology*
  • Molecular Structure
  • Piperazines / pharmacology*
  • Piperidines / chemical synthesis
  • Piperidines / pharmacokinetics
  • Piperidines / pharmacology
  • Pyridines / chemical synthesis
  • Pyridines / pharmacokinetics
  • Pyridines / pharmacology
  • Rats
  • Reverse Transcriptase Inhibitors / chemical synthesis*
  • Reverse Transcriptase Inhibitors / pharmacokinetics
  • Reverse Transcriptase Inhibitors / pharmacology
  • Structure-Activity Relationship

Substances

  • 1-((5-(((4-methyl-1-piperazinyl)carbonyl)amino)indol-2-yl)carbonyl)-4-(N-ethyl-N-(3-((1,1-dimethylethyl)amino)-6-fluoro-2-pyridinyl)amino)piperidine
  • 1-((5-methanesulfonamidoindol-2-yl)carbonyl)-4-(N-methyl-N-(3-((1,1-dimethylethyl)amino)-2-pyridinyl)amino)piperidine
  • 1-((5-methanesulfonamidoindol-2-yl-)carbonyl)-4-(N-ethyl-N-(3-((1,1-dimethylethyl)amino)-2-pyridinyl)amino)piperidine
  • Anti-HIV Agents
  • Indoles
  • Piperazines
  • Piperidines
  • Pyridines
  • Reverse Transcriptase Inhibitors
  • Delavirdine
  • HIV Reverse Transcriptase
  • atevirdine