Naphthyridinone (NTD) integrase inhibitors 4. Investigating N1 acetamide substituent effects with C3 amide groups

Bioorg Med Chem Lett. 2014 Jul 15;24(14):3104-7. doi: 10.1016/j.bmcl.2014.05.011. Epub 2014 May 16.

Abstract

A series of N1 acetamide substituted naphthyridinone HIV-1 integrase inhibitors have been explored to understand structure-activity relationships (SAR) with various C3 amide groups. Investigations were evaluated using integrase enzyme inhibition, antiviral activity and protein binding effects to optimize the sub-structures. Lipophilicity was also incorporated to understand ligand lipophilic efficiency as a function of the structural modifications. Three representative analogs were further examined in a peripheral blood mononuclear cell (PBMC) antiviral assay as well as in vitro and in vivo drug metabolism and pharmacokinetic studies.

Keywords: HIV-1; Integrase; Naphthyridinone.

MeSH terms

  • Acetamides / chemistry*
  • Amides / chemistry*
  • Dose-Response Relationship, Drug
  • HIV Integrase / metabolism*
  • HIV Integrase Inhibitors / chemical synthesis
  • HIV Integrase Inhibitors / chemistry
  • HIV Integrase Inhibitors / pharmacology*
  • Humans
  • Leukocytes, Mononuclear / drug effects
  • Leukocytes, Mononuclear / virology
  • Molecular Structure
  • Naphthyridines / chemical synthesis
  • Naphthyridines / chemistry
  • Naphthyridines / pharmacology*
  • Structure-Activity Relationship

Substances

  • Acetamides
  • Amides
  • HIV Integrase Inhibitors
  • Naphthyridines
  • HIV Integrase