Potent and selective inhibitors of an aspartyl protease-like endothelin converting enzyme identified in rat lung

J Med Chem. 1993 Feb 19;36(4):468-78. doi: 10.1021/jm00056a007.

Abstract

Two structurally distinct series of potent and selective inhibitors of an aspartyl protease-like endothelin converting enzyme (ECE) activity identified in the rat lung have been developed. Pepstatin A, which potently inhibits the rat lung ECE, served as the basis for the first series. Alternatively, selected renin inhibitors containing the dihydroxyethylene moiety were shown to be inhibitors of rat lung activity. Subsequent modifications improved inhibition of the rat lung ECE while eliminating renin activity. Both series of ECE inhibitors demonstrated a range of selectivity over Cathepsin D. Water-solubilizing moieties were appended onto selected compounds to facilitate in vivo testing. Partial reduction of the pressor response to exogenously administered Big ET-1 was observed with selected rat lung ECE inhibitors.

Publication types

  • Comparative Study

MeSH terms

  • Amino Acid Sequence
  • Amino Acids / chemistry
  • Animals
  • Aspartic Acid Endopeptidases / antagonists & inhibitors*
  • Blood Pressure / drug effects
  • Cathepsin D / antagonists & inhibitors
  • Cell Membrane / enzymology
  • Endothelin-Converting Enzymes
  • Endothelins / metabolism
  • Humans
  • Lung / enzymology*
  • Metalloendopeptidases
  • Molecular Sequence Data
  • Molecular Structure
  • Pepstatins / chemistry
  • Pepstatins / pharmacology
  • Protease Inhibitors / chemical synthesis*
  • Protease Inhibitors / chemistry
  • Protease Inhibitors / pharmacology
  • Rats
  • Renin / antagonists & inhibitors
  • Solubility
  • Structure-Activity Relationship
  • Water

Substances

  • Amino Acids
  • Endothelins
  • Pepstatins
  • Protease Inhibitors
  • Water
  • Streptomyces pepsin inhibitor
  • Aspartic Acid Endopeptidases
  • Renin
  • Cathepsin D
  • Metalloendopeptidases
  • Endothelin-Converting Enzymes
  • pepstatin
  • statine