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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

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

Jörg Pabel, Mark Faust, Cornelia Prehn, Babette Wörlein, Lars Allmendinger, Georg Höfner, Klaus T Wanner

ChemMedChem. 2012 Jul;7(7):1245-55.

PMID: 22544452

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 pIC(50) values of 5.78 and 5.87, respectively. Thus, as mGAT4 inhibitors, these compounds compare well with (S)-SNAP-5114 (pIC(50) =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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP157604552	(S)-SNAP-5114		157604-55-2	Price

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