title: New orally active dual enkephalinase inhibitors (DENKIs) for central and peripheral pain treatment.
abstract: Protecting enkephalins, endogenous opioid peptides released in response to nociceptive stimuli, is an innovative approach for acute and neuropathic pain alleviation. This is achieved by inhibition of their enzymatic degradation by two membrane-bound Zn-metallopeptidases, neprilysin (NEP, EC 3.4.24.11) and aminopeptidase N (APN, EC 3.4.11.2). Selective and efficient inhibitors of both enzymes, designated enkephalinases, have been designed that markedly increase extracellular concentrations and half-lives of enkephalins, inducing potent antinociceptive effects. Several chemical families of Dual ENKephalinase Inhibitors (DENKIs) have previously been developed but devoid of oral activity. We report here the design and synthesis of new pro-drugs, derived from co-drugs combining a NEP and an APN inhibitor through a disulfide bond with side chains improving oral bioavailability. Their pharmacological properties were assessed in various animal models of pain targeting central and/or peripheral opioid systems. Considering its efficacy in acute and neuropathic pain, one of these new DENKIs, 19-IIIa, was selected for clinical development.
authors.affiliation: Pharmaleads , Paris BioPark, 11 Rue Watt, 75013 Paris, France.
authors.forename: Hervé
authors.initials: H
authors.lastname: Poras
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Bonnard
authors.forename: Emilie
authors.initials: E
authors.lastname: Dangé
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Fournié-Zaluski
authors.forename: Bernard P
authors.initials: BP
authors.lastname: Roques
mesh_terms: D000284:Administration, Oral; D000700:Analgesics / Q000008:administration & dosage / Q000138:chemical synthesis / Q000493:pharmacokinetics; D000818:Animals; D018826:CD13 Antigens / Q000037:antagonists & inhibitors; D004220:Disulfides / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D004745:Enkephalins / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D015260:Neprilysin / Q000037:antagonists & inhibitors; D009437:Neuralgia / Q000188:drug therapy* / Q000201:enzymology; D010666:Phenylpropionates / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D011355:Prodrugs / Q000008:administration & dosage / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000627:therapeutic use; D011437:Propylamines; D011480:Protease Inhibitors / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000493:pharmacokinetics; D051381:Rats
chemical_list: C534222:1-(2-((1-ethoxycarbonyloxyethoxycarbonylmethyl)carbamoyl)-3-phenylpropyldisulfanylmethyl)-3-methylsulfanylpropylamine; D000700:Analgesics; D004220:Disulfides; D004745:Enkephalins; D010666:Phenylpropionates; D011355:Prodrugs; D011437:Propylamines; D011480:Protease Inhibitors; D018826:CD13 Antigens; D015260:Neprilysin