Phosphinic derivatives as new dual enkephalin-degrading enzyme inhibitors:Synthesis, biological properties, and antinociceptive activities

The development of dual inhibitors of the two zinc metallopeptidases, nepri lysin (neutral endopeptidase) and aminopeptidase N involved in the inactiva tion of the opioid peptides, enkephalins, represents an attractive physiolo gical approach in the search for new analgesics devoid of the major drawbac ks of morphine. Phosphinic compounds, corresponding to the general formula H3N+-CH(R-1)-P(O)(OH)-CH2-CH(R-2)-CONH-CH(R-3)-COO-, able to act as transit ion-state analogues and to fit the S-1, S-1', and S-2' subsites of both enz ymes were designed. Selection of the R-1, R-2, and R-3 residues for optimal recognition of these enzymes led to the first dual competitive inhibitors with K-i values in the nanomolar range for neprilysin and aminopeptidase N. These compounds induce potent analgesic responses after intracerebroventri cular or intravenous administrations in mice (hot plate test), and several of them were shown to be, at least, 10 times more potent than the previousl y described dual inhibitors.