Effect of several amino acid phosphonates and other compounds on rat brain and kidney peptidases

A series of N-terminal phosphonate derivatives, H2O3PCHPhNHR (R = Leu, Phe, Trp, and/or Tyr), were synthesized with the aim of mimicking phosphoramidon, a potent inhibitor of enkephalinase, while avoiding the lability of the scissile P-N bond. All of the N-phosphonobenzyl derivatives of the amino acids, including the substituted succinylhydrazobenzophenone compounds, were inactive toward rat brain aminopeptidase and rat kidney carboxypeptidase. The N-monobenzylphosphonobenzyl derivatives, PhCH2OPO(OH)CHPhNHR, of individual amino acids and several of the N-phosphonobenzyl dipeptides showed inhibition in the micromolar range toward the soluble exopeptidase but were inactive with both the brain and kidney endopeptidase.