Phosphinic tripeptides as dual angiotensin-converting enzyme C-domain and endothelin-converting enzyme-1 inhibitors

J Med Chem. 2010 Jan 14;53(1):208-20. doi: 10.1021/jm9010803.


A new series of phosphinic inhibitors able to interact with both angiotensin-converting enzyme (ACE) C-domain and endothelin-converting enzyme-1 (ECE-1), while sparing neprilysin (NEP), has been developed. The most potent and selective inhibitor in this series (compound 8(F2)) displays K(i) values of 0.65 nM, 150 nM, 14 nM and 6.7 microM toward somatic ACE C-domain, ACE N-domain, ECE-1, and NEP, respectively. Remarkably, in this series, the inhibitor's ability to discriminate between ECE-1 and NEP was observed to depend on the stereochemistry of the residue present in the inhibitor's P(1)' position. After iv administration, compound 8(F2) (10 mg/kg) lowered mean arterial blood pressure by 24 +/- 2 mmHg in spontaneously hypertensive rats, as compared with controls. Mixed ACE/ECE-1 inhibitor may lead to a new generation of vasopeptide inhibitors that should reduce the levels of angiotensin-II and endothelin-1, without interfering with bradykinin cleavage.

MeSH terms

  • Angiotensin-Converting Enzyme Inhibitors / chemical synthesis
  • Angiotensin-Converting Enzyme Inhibitors / chemistry
  • Angiotensin-Converting Enzyme Inhibitors / pharmacology*
  • Animals
  • Aspartic Acid Endopeptidases / antagonists & inhibitors*
  • Blood Pressure / drug effects
  • Dose-Response Relationship, Drug
  • Drug Evaluation, Preclinical
  • Endothelin-Converting Enzymes
  • Matrix Metalloproteinase Inhibitors
  • Metalloendopeptidases / antagonists & inhibitors*
  • Molecular Conformation
  • Neprilysin / antagonists & inhibitors
  • Oligopeptides / chemical synthesis
  • Oligopeptides / chemistry
  • Oligopeptides / pharmacology*
  • Peptidyl-Dipeptidase A / metabolism*
  • Rats
  • Rats, Inbred SHR
  • Stereoisomerism
  • Structure-Activity Relationship


  • Angiotensin-Converting Enzyme Inhibitors
  • Matrix Metalloproteinase Inhibitors
  • Oligopeptides
  • Peptidyl-Dipeptidase A
  • Aspartic Acid Endopeptidases
  • Metalloendopeptidases
  • Neprilysin
  • Endothelin-Converting Enzymes