95909-00-5Relevant 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.
beta -thiopropionyl-aminoacid derivatives and their use as beta -lactamase inhibitors
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, (2008/06/13)
PCT No. PCT/EP97/00516 Sec. 371 Date Jan. 13, 1999 Sec. 102(e) Date Jan. 13, 1999 PCT Filed Feb. 3, 1997 PCT Pub. No. WO97/30027 PCT Pub. Date Aug. 21, 1997A method of treatment of bacterial infections in humans or animals which comprises administering, in combination with a beta -lactam antibiotic, a therapeutically effective amount of an amino acid derivative of Formula (I) or a pharmaceutically acceptable salt, solvate or in vivo hydrolysable ester thereof, wherein: R is hydrogen, a salt forming cation or an in vivo hydrolysable ester-forming group; R1 is hydrogen, (C1-6)alkyl optionally substituted by up to three halogen atoms or by a mercapto, (C1-6)alkoxy, hydroxy, amino, nitro, carboxy, (C1-6)alkylcarbonyloxy, (C1-6)alkoxycarbonyl, formyl or (C1-6)alkylcarbonyl group, (C3-7)cycloalkyl, (C3-7)cycloalkyl(C2-6)alkyl, (C2-6)alkenyl, (C2-6)alkynyl, aryl, aryl(C1-6)alkyl, heterocyclyl or heterocyclyl(C1-6)alkyl; R2 is hydrogen, (C1-6)alkyl or aryl(C1-6)alkyl; R3 is hydrogen, (C1-6)alkyl optionally substituted by up to three halogen atoms, (C3-7)cycloalkyl, fused aryl(C3-7)cycloalkyl, (C3-7)cycloalkyl(C2-6)alkyl, (C2-6)alkenyl, (C2-6)alkynyl, aryl, aryl-(CHR10)m-X-(CHR11)n, heterocyclyl or heterocyclyl-(CHR10)m-X-(CHR11)n, where m is 0 to 3, n is 1 to 3, each R10 and R11 is independently hydrogen or (C1-4)alkyl and X is O, S(O)x where x is 0-2, or a bond; R4 is hydrogen, or an in vivo hydrolysable acyl group; and R5 and R6 are independently hydrogen and (C1-6)alkyl or together represent (CH2)p where p is 2 to 5. Some compounds are claimed per se.
1H NMR configurational correlation for retro-inverso dipeptides: application to the determination of the absolute configuration of "enkephalinase" inhibitors. Relationships between stereochemistry and enzyme recognition.
Fournie-Zaluski,Lucas-Soroca,Devin,Roques
, p. 751 - 757 (2007/10/02)
A stereospecific synthesis of thiorphan [N-[2(RS)-(mercaptomethyl)-1-oxo-3-phenylpropyl]glycine] and retro-thiorphan [3-[[1(RS)-(mercaptomethyl)-2-phenylethyl]amino]-3-oxopropanoic acid], two highly potent inhibitors of enkephalinase, a neutral endopeptidase involved in enkephalin metabolism, is reported. Due to a rapid isomerization process, derivatives of retro-thiorphan, which contains a 2-substituted malonyl moiety, cannot be separated by classical methods. However, a separation of the diastereoisomeric mixtures of these retro-thiorphan derivatives was achieved by HPLC. The absolute configuration of each isomer was determined by using an NMR configurational correlation. The inhibitory potency of the various inhibitors indicates that, in the thiorphan series, the affinity for enkephalinase is independent of the stereochemistry of the 2-(mercaptomethyl)-1-oxo-3-phenylpropyl moiety. In contrast, in the retro-thiorphan series a 100-fold difference in the inhibitory activity of the two enantiomers is observed. This indicates that there are large differences in the conformational behavior of the two series of inhibitors at the active site of the enzyme.
