European Journal of Medicinal Chemistry 2010-01-01

Azetidine derivatives as novel γ-aminobutyric acid uptake inhibitors: Synthesis, biological evaluation, and structure–activity relationship

Mark R. Faust, Georg Höfner, Jörg Pabel, Klaus T. Wanner, Mark R. Faust, Georg Höfner, Jörg Pabel, Klaus T. Wanner

Index: Eur. J. Med. Chem. 45 , 2453-66, (2010)

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Abstract

In this study azetidine derivatives representing conformationally constrained GABA or β-alanine analogs were evaluated for their potency as GABA-uptake inhibitors. The study comprised derivatives substituted in 2- as well as in 3-position with either an acetic acid moiety or a carboxylic acid function. In addition, azetidine derivatives bearing a tetrazole ring as a bioisosteric substitute for a carboxylic acid group were included. 3-Hydroxy-3-(4-methoxyphenyl)azetidine derivatives were explored as analogs of the known GABA-uptake inhibitor NNC-05-2045 exhibiting an azetidine ring instead of a piperidine ring present in the latter. Both, N-unsubstituted compounds as well as their N-alkylated lipophilic derivatives, were biologically evaluated for their affinity to the GAT-1 and GAT-3 transporters. Azetidin-2-ylacetic acid derivatives provided with a 4,4-diphenylbutenyl or 4,4-bis(3-methyl-2-thienyl)butenyl moiety as lipophilic residue were found to exhibit the highest potency at GAT-1 with IC 50 values of 2.83 ± 0.67 μM and 2.01 ± 0.77 μM, respectively. The most potent GAT-3 inhibitor among these compounds appeared to be the β-alanine analog 1-{2-[tris(4-methoxyphenyl)methoxy]ethyl}azetidine-3-carboxylic acid ( 12d) displaying an IC 50 value of 15.3 ± 4.5 μM. Whereas the tetrazole derivatives showed no potency as GABA-uptake inhibitors, the 3-hydroxy-3-(4-methoxyphenyl)azetidine derivatives exhibited moderate affinity to GAT-1 (compound 18b: IC 50 = 26.6 ± 3.3 μM) and to GAT-3 (compound 18e: IC 50 = 31.0 ± 4.7 μM).