Synthesis of novel inhibitors of the HIV-1 protease: difunctional enols of simple N-protected amino acids

Bioorg Med Chem. 1994 May;2(5):343-55. doi: 10.1016/s0968-0896(00)82191-4.

Abstract

A series of enol HIV-1 protease inhibitors which show competitive inhibition and the structure-activity relationship study which led to the design of these compounds are reported. By systematically modifying simple amino acids, Boc-Phe enol and Boc-Tyr enol derivatives yield nanomolar Kiapp values (Kiapp = 0.485 microM and Kiapp = 0.425 microM, respectively). These enols are of low molecular weight (< 500 g/mol) and of non-peptidic nature. The enols are synthesized in a one step chemical synthesis and modifications to increase their potency could easily be performed. Boc-Phe enol and Boc-Tyr enol showed low inhibitory effect on pepsin, Kiapps of 23 and 149 microM, respectively, and Boc-Phe enol showed a Kiapp of 20 microM for cathepsin D. Neither of these two compounds inhibited renin (< 10% inhibition at 200 microM).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acids / chemical synthesis
  • Amino Acids / chemistry
  • Amino Acids / pharmacology
  • Binding, Competitive
  • Cathepsin D / antagonists & inhibitors
  • HIV Protease Inhibitors / chemical synthesis*
  • HIV Protease Inhibitors / chemistry
  • HIV Protease Inhibitors / pharmacology
  • HIV-1 / enzymology*
  • In Vitro Techniques
  • Kinetics
  • Magnetic Resonance Spectroscopy
  • Molecular Structure
  • Pepsin A / antagonists & inhibitors
  • Renin / antagonists & inhibitors
  • Structure-Activity Relationship

Substances

  • Amino Acids
  • HIV Protease Inhibitors
  • Pepsin A
  • Renin
  • Cathepsin D