Skip to Main content Skip to Navigation
Journal articles

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.
Complete list of metadata

https://hal-cnrs.archives-ouvertes.fr/hal-03292704
Contributor : Colette Orange Connect in order to contact the contributor
Submitted on : Tuesday, July 20, 2021 - 3:23:32 PM
Last modification on : Tuesday, October 19, 2021 - 11:02:05 AM

Identifiers

Citation

Herve Poras, Elisabeth Bonnard, Emilie Dange, Marie-Claude Fournie-Zaluski, Bernard P. Roques. New Orally Active Dual Enkephalinase Inhibitors (DENKIs) for Central and Peripheral Pain Treatment. Journal of Medicinal Chemistry, American Chemical Society, 2014, 57 (13), pp.5748-5763. ⟨10.1021/jm500602h⟩. ⟨hal-03292704⟩

Share

Metrics

Record views

13