Dicarboxylic acid dipeptide neutral endopeptidase inhibitors

J Med Chem. 1995 May 12;38(10):1689-700. doi: 10.1021/jm00010a014.


The synthesis of three series of dicarboxylic acid dipeptide neutral endopeptidase 24.11 (NEP) inhibitors is described. In particular, the amino butyramide 21a exhibited potent NEP inhibitory activity (IC50 = 5.0 nM) in vitro and in vivo. Blood levels of 21a were determined using an ex vivo method by measuring plasma inhibitory activity in conscious rats, mongrel dogs, and cynomolgus monkeys. Free drug concentrations were 10-1500 times greater than the inhibitory constant for NEP over the course of a 6 h experiment. A good correlation of free drug concentrations was obtained when comparing values determined by the ex vivo analysis to those calculated from direct HPLC measurements. Plasma atrial natriuretic factor (exogenous) levels were elevated in rats and dogs after oral administration of 19a. Urinary volume and urinary sodium excretion were also potentiated in anesthetized dogs treated with 21a.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Atrial Natriuretic Factor / blood
  • Atrial Natriuretic Factor / pharmacology
  • Dicarboxylic Acids / chemistry
  • Dicarboxylic Acids / pharmacokinetics
  • Dicarboxylic Acids / pharmacology*
  • Dipeptides / chemistry
  • Dipeptides / pharmacokinetics
  • Dipeptides / pharmacology*
  • Diuresis / drug effects
  • Dogs
  • Macaca fascicularis
  • Male
  • Molecular Sequence Data
  • Natriuresis / drug effects
  • Neprilysin / antagonists & inhibitors*
  • Rats
  • Rats, Sprague-Dawley
  • Structure-Activity Relationship


  • Dicarboxylic Acids
  • Dipeptides
  • Atrial Natriuretic Factor
  • Neprilysin