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.

Determination of enantiomeric excess of nipecotic acid as 1‐(7‐nitrobenzo[c][1,2,5]oxadiazol‐4‐yl) derivatives

“…[1,2,5]oxadiazole-4-sulfonamide (DBD-F). The digital resolution is stated with an accuracy of ±0.15 Hz.…”

“…2 For example, tiagabine [(R)-2] and SK&F-89976A (3) are reuptake inhibitors for the subtype GAT1 for which the (R)-enantiomers are known to be more potent than the (S)-enantiomer [(S)-2: pIC 50 = 6.20 ± 0.13; (R)-2: pIC 50 = 6.88 ± 0.12; (S)-3: pIC 50 = 4.97 ± 0.10; (R)-3: pIC 50 = 5.49 ± 0.09]. 4,5 As can be seen from these examples and in the case of even higher enantioselectivities, it is necessary to use only highly enantiopure samples for the determination of the pharmacological data of novel chiral GABA reuptake inhibitors, as the false enantiomer will distort the resulting data the more it is present. 4,5 As can be seen from these examples and in the case of even higher enantioselectivities, it is necessary to use only highly enantiopure samples for the determination of the pharmacological data of novel chiral GABA reuptake inhibitors, as the false enantiomer will distort the resulting data the more it is present.…”

“…Therefore, we deemed derivative of 1 1-(7-nitrobenzo[c] [1,2,5]oxadiazol-4-yl)nipecotic acid (rac-5) more suitable for chiral analysis (Scheme 1). 20 The low-cost reagent 4fluoro-7-nitrobenzo[c] [1,2,5]oxadiazole (6, NBD-F) 21 required for the preparation of 5 is widely used for the analysis of amino acids like proline by HPLC, as it is known to allow the formation of stable derivatives under mild reaction conditions and to give rise to products with absorption wavelengths around 470 nm, allowing a reasonably selective UV/ Vis-detection.…”

“…2.1.3 | Synthesis4-Fluoro-7-nitrobenzo[c][1,2,5]oxadiazole (6, NBD-F) was synthesized according to the literature 24. The synthesis of 5 from 1 with 6 (NBD-F) was accomplished in analogy to the procedure published by Min et al for the…”

“…Nitrobenzo[c][1,2,5]oxadiazol-4-yl)piperidine-3-carboxylic acid (rac-5): According to GP with racnipecotic acid (rac-1) (26.0 mg, 0.201 mmol) in aqueous solution of Na 2 CO 3 (9.6 ml) and NBD-F (40.5 mg, 0.221 mmol) in CH 3 CN (3 ml). Yield: 57 mg (98%), red amorphous powder.…”