(S)-1-(Pent-4′-enoyl)-4-(hydroxymethyl)-azetidin-2-one derivatives as inhibitors of human fatty acid amide hydrolase (hFAAH): Synthesis, biological evaluation and molecular modelling

Joséphine Caruano, Marion Feledziak, Geoffray Labar, Catherine Michaux, Eric A. Perpète, Giulio G. Muccioli, Raphaël Robiette, Jacqueline Marchand-Brynaert

Résultats de recherche: Contribution à un journal/une revueArticle

Résumé

A series of lipophilic ester derivatives (2a-g) of (S)-1-(pent-4′-enoyl)-4-(hydroxymethyl)-azetidin-2-one has been synthesised in three steps from (S)-4-(benzyloxycarbonyl)-azetidin-2-one and evaluated as novel, reversible, β-lactamic inhibitors of endocannabinoid-degrading enzymes (human fatty acid amide hydrolase (hFAAH) and monoacylglycerol lipase (hMAGL)). The compounds showed IC50 values in the micromolar range and selectivity for hFAAH versus hMAGL. The unexpected 1000-fold decrease in activity of 2a comparatively to the known regioisomeric structure 1a (i.e. lipophilic chains placed on N1 and C3 positions of the β-lactam core) could be explained on the basis of docking studies into a revisited model of hFAAH active site, considering one or two water molecules in interaction with the catalytic triad.

langueAnglais
Pages654-662
Nombre de pages9
journalJournal of enzyme inhibition and medicinal chemistry
Volume29
Numéro5
Date de mise en ligne précoce9 oct. 2013
Les DOIs
étatPublié - 1 oct. 2014

Empreinte digitale

Monoacylglycerol Lipases
Endocannabinoids
beta-Lactams
Inhibitory Concentration 50
Catalytic Domain
Esters
Water
Enzymes
fatty-acid amide hydrolase

mots-clés

    Citer ceci

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    title = "(S)-1-(Pent-4′-enoyl)-4-(hydroxymethyl)-azetidin-2-one derivatives as inhibitors of human fatty acid amide hydrolase (hFAAH): Synthesis, biological evaluation and molecular modelling",
    abstract = "A series of lipophilic ester derivatives (2a-g) of (S)-1-(pent-4′-enoyl)-4-(hydroxymethyl)-azetidin-2-one has been synthesised in three steps from (S)-4-(benzyloxycarbonyl)-azetidin-2-one and evaluated as novel, reversible, β-lactamic inhibitors of endocannabinoid-degrading enzymes (human fatty acid amide hydrolase (hFAAH) and monoacylglycerol lipase (hMAGL)). The compounds showed IC50 values in the micromolar range and selectivity for hFAAH versus hMAGL. The unexpected 1000-fold decrease in activity of 2a comparatively to the known regioisomeric structure 1a (i.e. lipophilic chains placed on N1 and C3 positions of the β-lactam core) could be explained on the basis of docking studies into a revisited model of hFAAH active site, considering one or two water molecules in interaction with the catalytic triad.",
    keywords = "Docking, Fatty acid amide hydrolase, Rapid dilution, Reversible inhibition, β-lactam",
    author = "Jos{\'e}phine Caruano and Marion Feledziak and Geoffray Labar and Catherine Michaux and Perp{\`e}te, {Eric A.} and Muccioli, {Giulio G.} and Rapha{\"e}l Robiette and Jacqueline Marchand-Brynaert",
    year = "2014",
    month = "10",
    day = "1",
    doi = "10.3109/14756366.2013.837900",
    language = "English",
    volume = "29",
    pages = "654--662",
    journal = "Journal of enzyme inhibition and medicinal chemistry",
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    (S)-1-(Pent-4′-enoyl)-4-(hydroxymethyl)-azetidin-2-one derivatives as inhibitors of human fatty acid amide hydrolase (hFAAH): Synthesis, biological evaluation and molecular modelling. / Caruano, Joséphine; Feledziak, Marion; Labar, Geoffray; Michaux, Catherine; Perpète, Eric A.; Muccioli, Giulio G.; Robiette, Raphaël; Marchand-Brynaert, Jacqueline.

    Dans: Journal of enzyme inhibition and medicinal chemistry, Vol 29, Numéro 5, 01.10.2014, p. 654-662.

    Résultats de recherche: Contribution à un journal/une revueArticle

    TY - JOUR

    T1 - (S)-1-(Pent-4′-enoyl)-4-(hydroxymethyl)-azetidin-2-one derivatives as inhibitors of human fatty acid amide hydrolase (hFAAH): Synthesis, biological evaluation and molecular modelling

    AU - Caruano, Joséphine

    AU - Feledziak, Marion

    AU - Labar, Geoffray

    AU - Michaux, Catherine

    AU - Perpète, Eric A.

    AU - Muccioli, Giulio G.

    AU - Robiette, Raphaël

    AU - Marchand-Brynaert, Jacqueline

    PY - 2014/10/1

    Y1 - 2014/10/1

    N2 - A series of lipophilic ester derivatives (2a-g) of (S)-1-(pent-4′-enoyl)-4-(hydroxymethyl)-azetidin-2-one has been synthesised in three steps from (S)-4-(benzyloxycarbonyl)-azetidin-2-one and evaluated as novel, reversible, β-lactamic inhibitors of endocannabinoid-degrading enzymes (human fatty acid amide hydrolase (hFAAH) and monoacylglycerol lipase (hMAGL)). The compounds showed IC50 values in the micromolar range and selectivity for hFAAH versus hMAGL. The unexpected 1000-fold decrease in activity of 2a comparatively to the known regioisomeric structure 1a (i.e. lipophilic chains placed on N1 and C3 positions of the β-lactam core) could be explained on the basis of docking studies into a revisited model of hFAAH active site, considering one or two water molecules in interaction with the catalytic triad.

    AB - A series of lipophilic ester derivatives (2a-g) of (S)-1-(pent-4′-enoyl)-4-(hydroxymethyl)-azetidin-2-one has been synthesised in three steps from (S)-4-(benzyloxycarbonyl)-azetidin-2-one and evaluated as novel, reversible, β-lactamic inhibitors of endocannabinoid-degrading enzymes (human fatty acid amide hydrolase (hFAAH) and monoacylglycerol lipase (hMAGL)). The compounds showed IC50 values in the micromolar range and selectivity for hFAAH versus hMAGL. The unexpected 1000-fold decrease in activity of 2a comparatively to the known regioisomeric structure 1a (i.e. lipophilic chains placed on N1 and C3 positions of the β-lactam core) could be explained on the basis of docking studies into a revisited model of hFAAH active site, considering one or two water molecules in interaction with the catalytic triad.

    KW - Docking

    KW - Fatty acid amide hydrolase

    KW - Rapid dilution

    KW - Reversible inhibition

    KW - β-lactam

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    DO - 10.3109/14756366.2013.837900

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    VL - 29

    SP - 654

    EP - 662

    JO - Journal of enzyme inhibition and medicinal chemistry

    T2 - Journal of enzyme inhibition and medicinal chemistry

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    SN - 1475-6366

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