HIV-1 Protease Inhibitors Based on Hydroxyethylene Dipeptide Isosteres: An Investigation Into the Role of the P1' Side Chain on Structure-Activity

J Med Chem. 1992 May 15;35(10):1702-9. doi: 10.1021/jm00088a004.

Abstract

A systematic investigation was undertaken to determine the role of the P1' sidechain in a series of hydroxyethylene isostere based inhibitors of HIV-1 protease. Substitution and homologation of the benzyl P1' side chain of the Phe-Phe isostere based pseudo peptides 1 (L-682,679) and 2 (L-685,434) with various heteroalkyl groups leads to a series of extremely potent inhibitors of the enzyme. Several examples of the most potent inhibitors were very effective in an ex vivo cell based viral spread assay using human H9 T-lymphocytes and the IIIb isolate of HIV-1. Compound 19 is 120 times more potent than 1 and 16 times more potent than 2 in inhibiting the spread of infection in this assay.

MeSH terms

  • Antiviral Agents / chemistry
  • Antiviral Agents / pharmacology*
  • Dipeptides / chemical synthesis
  • Dipeptides / chemistry
  • Dipeptides / pharmacology*
  • Ethylenes / chemical synthesis
  • Ethylenes / pharmacology*
  • HIV Protease / metabolism
  • HIV Protease Inhibitors*
  • HIV-1 / enzymology*
  • HIV-1 / growth & development
  • Humans
  • Indoles / chemistry
  • Indoles / pharmacology
  • Oligopeptides / chemistry
  • Oligopeptides / pharmacology
  • Phosphates / chemistry
  • Protease Inhibitors / chemistry
  • Protease Inhibitors / pharmacology
  • Solubility
  • Structure-Activity Relationship
  • T-Lymphocytes / microbiology

Substances

  • Antiviral Agents
  • Dipeptides
  • Ethylenes
  • HIV Protease Inhibitors
  • Indoles
  • Oligopeptides
  • Phosphates
  • Protease Inhibitors
  • L 682679
  • L 685434
  • hydroxyethylene
  • HIV Protease