title: Long lasting antinociceptive properties of enkephalin degrading enzyme (NEP and APN) inhibitor prodrugs.
abstract: Prodrugs of phosphinic dual inhibitors of the enkephalin degrading enzymes, neutral endopeptidase (NEP) and aminopeptidase N (APN), corresponding to the formula H(3)N(+)CH(R(1))P(O)(OR)CH(2)CH(CH(2)Bip)CONHCH(CH(3))COOCH(2)Ph, with R(1) = CH(3) 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 ( approximately 2 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) approximately 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.
authors.affiliation: Département de Pharmacochimie Moléculaire et Structurale, INSERM U266, CNRS UMR 8600, Paris Cedex 06, France.
authors.forename: H
authors.initials: H
authors.lastname: Chen
authors.forename: F
authors.initials: F
authors.lastname: Noble
authors.forename: B P
authors.initials: BP
authors.lastname: Roques
authors.forename: M C
authors.initials: MC
authors.lastname: Fournié-Zaluski
mesh_terms: D000626:Aminopeptidases / Q000037:antagonists & inhibitors*; D000700:Analgesics / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001711:Biotransformation; D001921:Brain / Q000378:metabolism; D018826:CD13 Antigens / Q000037:antagonists & inhibitors*; D002851:Chromatography, High Pressure Liquid; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006868:Hydrolysis; D066298:In Vitro Techniques; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D008297:Male; D051379:Mice; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D010147:Pain Measurement; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D000700:Analgesics; D004791:Enzyme Inhibitors; D011355:Prodrugs; D000626:Aminopeptidases; C025579:enkephalin degrading enzyme; D018826:CD13 Antigens; D015260:Neprilysin