Long lasting antinociceptive properties of enkephalin degrading enzyme (NEP and APN) inhibitor prodrugs

Prodrugs of phosphinic dual inhibitors of the enkephalin degrading enzymes, neutral endopeptidase (NEP) and aminopeptidase N (APN), corresponding to the formula H3N+CH(R-1)P(O)(OR)CH2CH(CH(2)Bip)CONHCH(CH3)COOCH2Ph, with R-1 = CH3 or Ph and R being a benzyl ester, a S-acyl-2-thioethyl derivative, or an acyloxyalkyl group, were synthesized to improve the poor central bioavailability of their precursors. As expected, these compounds (50 mg/kg, iv or ip) induced long lasting (similar to2 h) antinociceptive responses in the hot plate test in mice with a ceiling effect varying between 25 and 42% of analgesia. A very rapid hydrolysis of the carboxylate ester contrasting with a slow deprotection of the phosphinate group (t(1/2) similar to 1 h) was observed in serum while 80% of free drug was obtained after 1 h incubation with brain membranes. These results account for the long duration of action observed with these prodrugs.