A series of potent HIV-1 protease inhibitors containing a hydroxyethyl secondary amine transition state isostere: synthesis, enzyme inhibition, and antiviral activity

J Med Chem. 1992 Jul 10;35(14):2525-33. doi: 10.1021/jm00092a002.


A series of HIV-1 protease inhibitors containing a novel hydroxyethyl secondary amine transition state isostere has been synthesized. The compounds exhibit a strong preference for the (R) stereochemistry at the transition state hydroxyl group. Molecular modeling studies with the prototype compound 11 have provided important insights into the structural requirements for good inhibitor-active site binding interaction. N-Terminal extension of 11 into the P2-P3 region led to the discovery of 19, the most potent enzyme inhibitor in the series (IC50 = 5.4 nM). 19 was shown to have potent antiviral activity in cultured MT-4 human T-lymphoid cells. Comparison of analogs of 19 with analogs of 1 (Ro31-8959) demonstrates that considerably different structure-activity relationships exist between these two subclasses of hydroxyethylamine HIV-protease inhibitors.

MeSH terms

  • Amino Acid Sequence
  • Antiviral Agents / chemical synthesis*
  • Antiviral Agents / pharmacology
  • Binding Sites
  • Cells, Cultured
  • Enzyme-Linked Immunosorbent Assay
  • Ethylamines / chemistry
  • Ethylamines / pharmacology*
  • HIV Core Protein p24 / analysis
  • HIV Protease / metabolism
  • HIV Protease Inhibitors*
  • HIV-1 / enzymology*
  • Humans
  • Mass Spectrometry
  • Models, Molecular
  • Molecular Sequence Data
  • Protease Inhibitors / chemical synthesis*
  • Protease Inhibitors / pharmacology


  • Antiviral Agents
  • Ethylamines
  • HIV Core Protein p24
  • HIV Protease Inhibitors
  • Protease Inhibitors
  • HIV Protease