Inhibitors of HIV-1 attachment: The discovery and structure-activity relationships of tetrahydroisoquinolines as replacements for the piperazine benzamide in the 3-glyoxylyl 6-azaindole pharmacophore

Bioorg Med Chem Lett. 2016 Jan 1;26(1):160-7. doi: 10.1016/j.bmcl.2015.11.009. Epub 2015 Nov 5.

Abstract

6,6-Fused ring systems including tetrahydroisoquinolines and tetrahydropyrido[3,4-d]pyrimidines have been explored as possible replacements for the piperazine benzamide portion of the HIV-1 attachment inhibitor BMS-663068. In initial studies, the tetrahydroisoquinoline compounds demonstrate sub-nanomolar activity in a HIV-1 pseudotype viral infection assay used as the initial screen for inhibitory activity. Analysis of SARs and approaches to optimization for an improved drug-like profile are examined herein.

Keywords: Attachment; BMS-663068; Entry; HIV-1; Tetrahydroisoquinoline; Tetrahydropyrido[3,4-d]pyrimidines.

MeSH terms

  • Aza Compounds / chemistry*
  • Benzamides / chemistry*
  • Cell Survival / drug effects
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • HIV Envelope Protein gp120 / antagonists & inhibitors
  • HIV Envelope Protein gp120 / genetics
  • HIV Fusion Inhibitors / chemical synthesis
  • HIV Fusion Inhibitors / chemistry*
  • HIV Fusion Inhibitors / pharmacology*
  • HIV Infections / drug therapy
  • HIV Infections / genetics
  • HIV-1 / drug effects*
  • HeLa Cells
  • Humans
  • Indoles / chemistry*
  • Molecular Structure
  • Piperazines / chemistry*
  • Structure-Activity Relationship
  • Tetrahydroisoquinolines / chemical synthesis
  • Tetrahydroisoquinolines / chemistry
  • Tetrahydroisoquinolines / pharmacology*
  • Virus Attachment / drug effects*
  • Virus Replication / drug effects

Substances

  • 6-azaindole
  • Aza Compounds
  • Benzamides
  • HIV Envelope Protein gp120
  • HIV Fusion Inhibitors
  • Indoles
  • Piperazines
  • Tetrahydroisoquinolines