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

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.