The peripheral endogenous
opioid system is critically involved in neuropathic and inflammatory
pain generation as suggested by the modulation of
opioid receptors expression and
enkephalins (ENKs) release observed in these painful conditions. Accordingly, an innovative approach in the treatment of these nocifensive events is to increase and maintain high local concentrations of extracellular
pain-evoked ENKs, by preventing their physiological enzymatic inactivation by two Zn
metallopeptidases, the
neutral endopeptidase (NEP,
neprilysin, EC 3.4.24.11) and the neutral
aminopeptidase (APN, EC 3.4.11.2). With this aim, new orally active dual
ENKephalinase inhibitors (DENKIs) were designed as soluble
prodrugs by introducing a N-terminal cleavable
carbamate in the previously described aminophosphinic inhibitors. This induces long-lasting antinociceptive responses after
oral administration, in various rodent models of inflammatory and
neuropathic pain. These responses are mediated through stimulation of peripheral
opioid receptors by DENKIs-protected ENKs as demonstrated by
naloxone methiodide reversion. In all tested models, the most efficient
prodrug 2a (
PL265) was active, at least during 150-180 min, after single
oral administration of 25-50 mg/kg in mice and of 100-200 mg/kg in rats. In models of
neuropathic pain, both
hyperalgesia and
allodynia were markedly reduced. Interestingly, combination of inactive doses of 2a (
PL265) and of the anti-epileptic drug
gabapentin had synergistic effect on
neuropathic pain. Pharmacokinetic studies of 2a (
PL265) in rats show that the active drug is the only generated metabolite produced. These encouraging results have made 2a (
PL265) a suitable candidate for clinical development.