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.

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

“…The recruitment of peripheral opioid receptors was confirmed by previous use of methyl naloxonium antagonist [22,23].…”

“…Therefore, the N-Isopropylcarbonyloxyethylcarbamate group was introduced in the DENKIs series 1ae1g previously described [22] (Scheme 1), leading to compounds 2ae2g. In addition, these new pro-drugs were esterified or not on the C-terminal position (see formula in Table 2).…”

“…These DENKIs have shown antinociceptive properties in various animal models of pain but were only active after iv administration [11]. A dramatic improvement in their bioavailability was achieved by decreasing the lipophilicity of drug and ester pro-drug moieties, leading to the DENKI 1-(2-(1-Ethoxycarbonyloxy-ethoxycarbonylmethyl)-carbamoyl)-3-phenyl-propyldisulfanylmethyl)-3-methylsulfanylpropylammonium fumarate 1a, designated PL37 [22,25] (Scheme 1). This compound is highly active per os and iv on severe acute central pain as well as on inflammatory and neuropathic pain [22].…”

The Cerebrospinal Fluid in Severe Pain Conditions : Clinical, Pharmacological and Proteomic Aspects

“…Using "AGT SERPINA1 HP SERPINF1" as entry for query genes and using the "physical" filtering option (i.e., only including interactions with evidence of the proteins physically touching), an interaction map was generated (Figure 19). The map features two known pain-related genes (highlighted in grey): 1) MME codes for neprilysin, which is important for the destruction of opioid peptides [190], and MME interacts with AGT (codes for angiotensinogen); 2) APOE codes for apolipoprotein E, an isoform of which (spot 3107) has VIP=1.53 (see protein table in appended Paper IV) and interacts with haptoglobin.…”

“… The RAS-system of the CNS (angiotensinogen)  Inflammation (alpha-1-antitrypsin and haptoglobin)  Neuroprotective compensatory reactions (PEDF)  Repair attempts (modulating apolipoprotein E, which is secreted from astrocytes and microglia, has been claimed to potentially provide therapeutic approaches for several neurological disorders [83]; apolipoprotein E is a CSF-enriched protein, see section 1.6.2)  Dysfunctional endogenous opioid function (protecting enkephalins by inhibiting neprilysin has recently been called an "innovative approach for acute and neuropathic pain alleviation" [190]; this is of course also a potentially interesting link to the findings of Paper III concerning BE) This is of course, to say the least, highly speculative but it is nonetheless arguably a plausible broad picture. It is here that neurobiologists need to step in and turn such hypothesisgenerating ideas into carefully designed hypothesis-driven neurobiological research.…”