Modulation of disulfide dual ENKephalinase inhibitors (DENKIs) activity by a transient N-protection for pain alleviation by oral route

• Published in: European journal of medicinal chemistry 2015-09, Vol.102, p.58-67
• Main Authors: Poras, Hervé, Bonnard, Elisabeth, Fournié-Zaluski, Marie-Claude, Roques, Bernard P.
• Format: Article
• Language: English
• Subjects: Administration, Oral; Analgesics - administration & dosage; Analgesics - chemistry; Analgesics - pharmacology; Animals; Chemical Sciences; Disulfides - administration & dosage; Disulfides - chemistry; Disulfides - pharmacology; Endogenous opioids; Inflammation; Life Sciences; Male; Medicinal Chemistry; Mice; Mice, Inbred Strains; Neprilysin - antagonists & inhibitors; Neprilysin - metabolism; Neurons and Cognition; Neuropathic pain; Oral administration; Pain - drug therapy; Pain Measurement; Peripheral analgesia; Protease Inhibitors - administration & dosage; Protease Inhibitors - chemistry; Protease Inhibitors - pharmacology
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2015.07.027

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 (NH3+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. [Display omitted] •Novel NEP-APN disulfide pro-drug inhibitors were designed.•Their transient protection involves the substitution of the amino group.•These compounds were efficient per-os in peripheral pain with long lasting effects.•These compounds were completely inactive in acute centrally-controlled pain.•They protect the pain-induced release of enkephalins at the site of injury.