Synthesis and antiviral activity of a series of HIV-1 protease inhibitors with functionality tethered to the P1 or P1' phenyl substituents: X-ray crystal structure assisted design

J Med Chem. 1992 May 15;35(10):1685-701. doi: 10.1021/jm00088a003.


By tethering of a polar hydrophilic group to the P1 or P1' substituent of a Phe-based hydroxyethylene isostere, the antiviral potency of a series of HIV protease inhibitors was improved. The optimum enhancement of anti-HIV activity was observed with the 4-morpholinylethoxy substituent. The substituent effect is consistent with a model derived from inhibitor docked in the crystal structure of the native enzyme. An X-ray crystal structure of the inhibited enzyme determined to 2.25 A verifies the modeling predictions.

MeSH terms

  • Binding Sites
  • Cells, Cultured
  • Drug Design*
  • Enzyme-Linked Immunosorbent Assay
  • HIV Protease / metabolism
  • HIV Protease Inhibitors*
  • HIV-1 / drug effects
  • HIV-1 / enzymology*
  • Humans
  • Models, Molecular
  • Morpholines / chemistry
  • Morpholines / pharmacology
  • Peptides / chemistry
  • Peptides / pharmacology
  • Protease Inhibitors / chemical synthesis*
  • Protease Inhibitors / pharmacology
  • Simian Immunodeficiency Virus / drug effects
  • X-Ray Diffraction


  • HIV Protease Inhibitors
  • Morpholines
  • Peptides
  • Protease Inhibitors
  • L 689502
  • HIV Protease