%0 Journal Article %T New Orally Active Dual Enkephalinase Inhibitors (DENKIs) for Central and Peripheral Pain Treatment %+ Pharmaleads %+ Unité de Technologies Chimiques et Biologiques pour la Santé (UTCBS - UM 4 (UMR 8258 / U1022)) %A Poras, Herve %A Bonnard, Elisabeth %A Dange, Emilie %A Fournie-Zaluski, Marie-Claude %A Roques, Bernard P. %< avec comité de lecture %@ 0022-2623 %J Journal of Medicinal Chemistry %I American Chemical Society %V 57 %N 13 %P 5748-5763 %8 2014 %D 2014 %R 10.1021/jm500602h %K OPIOID RECEPTOR AGONISTS %K DEGRADING ENZYMES %K NEUROPATHIC PAIN %K ENDOGENOUS ENKEPHALINS %K PEPTIDASE INHIBITORS %K FORMALIN TEST %K RAT %K POTENT %K MICE %K MODEL %Z Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology %Z Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]Journal articles %X 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. %G English %L hal-03292704 %U https://cnrs.hal.science/hal-03292704 %~ UNIV-PARIS5 %~ ENSCP %~ CNRS %~ ENSC-PARIS %~ PARISTECH %~ INC-CNRS %~ PSL %~ UNIV-PARIS %~ UP-SANTE %~ ENSCP-PSL %~ UTCBS %~ TEST2-HALCNRS