Development of an (S)-1-{2-[Tris(4-methoxyphenyl)methoxy]ethyl}piperidine-3-carboxylic acid [(S)-SNAP-5114] Carba Analogue Inhibitor for Murine γ-Aminobutyric Acid Transporter Type 4

Authors

  • Dr. Jörg Pabel,

    1. Department für Pharmazie—Zentrum für Pharmaforschung, Ludwig-Maximilians-Universität München, Butenandtstraße 5-13, 81377 München (Germany)
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  • Dr. Mark Faust,

    1. 3M ESPE AG, ESPE Platz, 82229 Seefeld (Germany)
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  • Dr. Cornelia Prehn,

    1. Institute for Experimental Genetics, Genome Analysis Center, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstädter Landstraße 1, 85764 Neuherberg (Germany)
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  • Dr. Babette Wörlein,

    1. 3M ESPE AG, ESPE Platz, 82229 Seefeld (Germany)
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  • Dr. Lars Allmendinger,

    1. Department für Pharmazie—Zentrum für Pharmaforschung, Ludwig-Maximilians-Universität München, Butenandtstraße 5-13, 81377 München (Germany)
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  • Dr. Georg Höfner,

    1. Department für Pharmazie—Zentrum für Pharmaforschung, Ludwig-Maximilians-Universität München, Butenandtstraße 5-13, 81377 München (Germany)
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  • Prof. Dr. Klaus T. Wanner

    Corresponding author
    1. Department für Pharmazie—Zentrum für Pharmaforschung, Ludwig-Maximilians-Universität München, Butenandtstraße 5-13, 81377 München (Germany)
    • Department für Pharmazie—Zentrum für Pharmaforschung, Ludwig-Maximilians-Universität München, Butenandtstraße 5-13, 81377 München (Germany)
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Abstract

A series of GABA uptake inhibitors related to (S)-1-{2-[tris(4-methoxyphenyl)methoxy]ethyl}piperidine-3-carboxylic acid [(S)-SNAP-5114], the most potent mGAT4 inhibitor known so far, were synthesized and biologically evaluated for their inhibitory potency at the four GABA uptake transporters mGAT1–4 stably expressed in HEK-293 cell lines. New analogues were developed with potencies that are similar to or slightly higher than those of current mGAT4 inhibitors, but with distinctly improved chemical stability. (S)-Nipecotic acid derivatives possessing a 2-[1-(4-methoxy-2-methylphenyl)-1,1-bis(4-methoxyphenyl)methoxy]ethyl (DDPM-859) or a 4,4,4-tris(4-methoxyphenyl)but-2-en-1-yl moiety (DDPM-1457) were found to exhibit pIC50 values of 5.78 and 5.87, respectively. Thus, as mGAT4 inhibitors, these compounds compare well with (S)-SNAP-5114 (pIC50=5.71), but are far more stable than the latter. Moreover, DDPM-859 displays a more favorable subtype selectivity for mGAT4 versus mGAT3 than does (S)-SNAP-5114.

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