Abstract
| - Prodrugs of phosphinic dual inhibitors of the enkephalin degrading enzymes, neutral endopeptidase (NEP) and aminopeptidase N (APN), corresponding to the formula H3N+CH(R1)P(O)(OR)CH2CH(CH2Bip)CONHCH(CH3)COOCH2Ph, with R1 = CH3 or Ph and R being abenzyl ester, a S-acyl-2-thioethyl derivative, or an acyloxyalkyl group, were synthesized toimprove the poor central bioavailability of their precursors. As expected, these compounds (50mg/kg, iv or ip) induced long lasting (∼2 h) antinociceptive responses in the hot plate test inmice with a ceiling effect varying between 25 and 42% of analgesia. A very rapid hydrolysis ofthe carboxylate ester contrasting with a slow deprotection of the phosphinate group (t1/2 ∼ 1 h)was observed in serum while 80% of free drug was obtained after 1 h incubation with brainmembranes. These results account for the long duration of action observed with these prodrugs.
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