title: Modulation of disulfide dual ENKephalinase inhibitors (DENKIs) activity by a transient N-protection for pain alleviation by oral route.
abstract: The endogenous opioid system, essentially constituted by two opioid receptors which are stimulated by the natural internal effectors enkephalins (Met-enkephalin and Leu-enkephalin), is present at the different sites (peripheral, spinal, central) of the control of pain. We have demonstrated that the protection of the enkephalin inactivation by the two metallopeptidases (neprilysin and neutral aminopeptidase) increases their local concentration selectively induced by pain stimuli triggering analgesic responses. With the aim of increasing the orally antinociceptive responses of the previously described disulfide DENKIs ( [Formula: see text] CH(R1)CH2-S-S-CH2-C(R2R3)CONHCH(R4)COOR5), we designed new pro-drugs, in the same chemical series, with a transient protection of the free amino group by an acyloxyalkyl carbamate, giving rise to ((CH3)2CHCO2CH(CH3)OCONHCH(R1)CH2-S-S-CH2-C(R2R3)CONHCH(R4)COOR5) pro-drugs 2a-2g. These compounds were easily prepared from their parent analogs, with a good yield. They were tested per os and shown to be highly efficient in peripherally-controlled inflammatory and neuropathic pain with long lasting effects but completely inactive in the acute centrally-controlled hot plate test, a model of pain by excess of nociception. This demonstrates that DENKIs are able to relieve pain at its source thanks to the increase of enkephalin levels.
authors.affiliation: Pharmaleads, Paris BioPark, 11 rue Watt, 75013 Paris, France. Electronic address: herve.poras@pharmaleads.com.
authors.forename: Hervé
authors.initials: H
authors.lastname: Poras
authors.affiliation: Pharmaleads, Paris BioPark, 11 rue Watt, 75013 Paris, France. Electronic address: elisabeth.bonnard@pharmaleads.com.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Bonnard
authors.affiliation: Pharmaleads, Paris BioPark, 11 rue Watt, 75013 Paris, France. Electronic address: marie-claude.fournie-zaluski@pharmaleads.com.
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Fournié-Zaluski
authors.affiliation: Pharmaleads, Paris BioPark, 11 rue Watt, 75013 Paris, France; Université Paris-Descartes, 4 Avenue de l'Observatoire, 75006 Paris, France. Electronic address: bernard.roques@pharmaleads.com.
authors.forename: Bernard P
authors.initials: BP
authors.lastname: Roques
mesh_terms: D000284:Administration, Oral; D000700:Analgesics / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D004220:Disulfides / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D015260:Neprilysin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010146:Pain / Q000188:drug therapy*; D010147:Pain Measurement; D011480:Protease Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000700:Analgesics; D004220:Disulfides; D011480:Protease Inhibitors; D015260:Neprilysin
keywords: Endogenous opioids; Inflammation; Neuropathic pain; Oral administration; Peripheral analgesia