Design and synthesis of potent, selective inhibitors of endothelin-converting enzyme

J Med Chem. 1998 Apr 23;41(9):1513-23. doi: 10.1021/jm970787c.


Endothelin-1 is the most potent peptidic vasoconstrictor discovered to date. The final step of posttranslational processing of this peptide is the conversion of its precursor by endothelin-converting enzyme-1 (ECE-1), a metalloprotease which displays high amino acid sequence identity with neutral endopeptidase 24.11 (NEP) especially at the catalytic center. A series of potent and selective arylacetylene-containing ECE-1 inhibitors have been prepared. (S, S)-3-Cyclohexyl-2-[[5-(2, 4-difluorophenyl)-2-[(phosphonomethyl)amino]pent-4-ynoyl]amino] propio nic acid (47), an arylacetylene amino phosphonate dipeptide, was found to inhibit ECE-1 and NEP with IC50 values of 14 nM and 2 microM, respectively. Similarly, (S)-[[1-[(2-biphenyl-4-ylethyl)carbamoyl]-4-(2-fluorophenyl)but-3- yny l]amino]methyl]phosphonic acid (56), an arylacetylene amino phosphonate amide, had IC50's of 33 nM and 6.5 microM for ECE-1 and NEP, respectively. Slight modification of the aryl moiety was found to have dramatic effects on ECE-1/NEP selectivity. The 2-fluoro dipeptide analogue, (S, S)-2-[[5-(2-fluorophenyl)-2-[(phosphonomethyl)amino]pent-4-ynoyl]+ ++amin o]-4-methylpentanoic acid (40), showed a 72-fold selectivity for ECE-1 over NEP, while the 3-fluoro dipeptide analogue, (S, S)-2-[[5-(3-fluorophenyl)-2-[(phosphonomethyl)amino]pent-4-ynoyl]+ ++amin o]-4-methylpentanoic acid (22), was equipotent for ECE-1 and NEP. Several of these inhibitors were shown to be potent in blocking ET-1 production in vivo as demonstrated by the big ET-1-induced pressor response in rats. These potent inhibitors are the most selective for ECE-1 reported to date and are envisaged to have a variety of therapeutic applications.

Publication types

  • Comparative Study

MeSH terms

  • Acetylene / analogs & derivatives
  • Acetylene / chemical synthesis*
  • Acetylene / chemistry
  • Acetylene / pharmacology
  • Amino Acid Sequence
  • Animals
  • Aspartic Acid Endopeptidases / antagonists & inhibitors*
  • Blood Pressure / drug effects
  • CHO Cells
  • Cricetinae
  • Drug Design*
  • Endothelin-1 / antagonists & inhibitors
  • Endothelin-1 / pharmacology
  • Endothelin-Converting Enzymes
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Male
  • Metalloendopeptidases
  • Molecular Sequence Data
  • Neprilysin / antagonists & inhibitors
  • Organophosphonates / chemical synthesis*
  • Organophosphonates / chemistry
  • Organophosphonates / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Recombinant Proteins / antagonists & inhibitors
  • Structure-Activity Relationship


  • Endothelin-1
  • Enzyme Inhibitors
  • Organophosphonates
  • Recombinant Proteins
  • Aspartic Acid Endopeptidases
  • Metalloendopeptidases
  • Neprilysin
  • ECE1 protein, human
  • Endothelin-Converting Enzymes
  • Acetylene