158293-54-0Relevant academic research and scientific papers
New orally active dual enkephalinase inhibitors (DENKIs) for central and peripheral pain treatment
Poras, Hervé,Bonnard, Elisabeth,Dangé, Emilie,Fournié-Zaluski, Marie-Claude,Roques, Bernard P.
, p. 5748 - 5763 (2014/08/05)
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.
AMINOACID DERIVATIVES CONTAINING A DISULFANYL GROUP IN THE FORM OF MIXED DISULFANYL AND AMINOPEPTIDASE N INHIBITORS
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Page/Page column 9, (2009/01/24)
The invention relates to novel compounds of formula (I): H2N-CH(R1)-CH2-S-S-CH2-CH(R2)-CONH-R5, wherein R1 is a hydrocarbon chain, phenyl or benzyl radical, methylene radical substituted by a 5 or 6 atom heterocycle; R2 is a phenyl or benzyl radical, a 5 or 6 atom aromatic heterocycle, methylene group substituted by a 5 or 6 atom heterocycle; R5 is a CH(R3)-COOR4 radical, wherein R3 is hydrogen, an OH or OR group, a saturated hydrocarbon group, a phenyl or benzyl radical and OR4 is hydrophile ester, or 5 or 6 membered heterocycle comprising several heteroatoms selected from a group consisting of nitrogen, sulphur and oxygen, with at least two nitrogene atoms, wherein said heterocycle is substitutable by an alkyl C1-C6, phenyl or benzyl radical. The use of the inventive compounds in the form of drugs, a pharmaceutical composition comprising said compounds, a pharmaceutically acceptable excipient, the use in conjunction of at least one type of cannabinoid derivative for potentiating the analgesic and antidepressant effect of the novel compounds of formula (I) and/or morphine or the derivatives thereof are also disclosed.
