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Kerscher-Hack, Silke; Renukappa-Gutke, Thejavathi; Höfner, Georg; Wanner, Klaus T. (2016): Synthesis and biological evaluation of a series of N-alkylated imidazole alkanoic acids as mGAT3 selective GABA uptake inhibitors. In: European Journal of Medicinal Chemistry, Vol. 124: pp. 852-880
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Abstract

In this paper, we report the synthesis and biological evaluation of a series of 1,5- and 1,4-substituted derivatives of 1H-imidazol-4-ylacetic acid, a series of 1,2-substituted 3-(1H-imidazol-2-yl)propanoic acid and an N-substituted (2E)-3-(1H-imidazol-2-yl)prop-2-enoic acid as new mGAT3 inhibitors. The lipophilic moieties attached to the N-atom of the parent structures were delineated from the 2-[9-(4-methoxypheny1)-9H-fluoren-9-yl]oxyethyl residue, known from a prototypic mGAT3 inhibitor. For the structure-activity-relationship studies, the spacer between the N-atom of the imidazole ring and the 2[9-(4-methoxyphenyl)-9H-fluoren-9-yl] moiety was varied in length from three to six atoms, and in nature being either a pure saturated or unsaturated alkyl chain or an alkyl chain containing up to two ether functions. The compounds were characterized for inhibitory potencies at mouse GABA transporter proteins mGAT1-mGAT4. Among the 1,2-substituted compounds, the N-alkylated (2E)-3-(1H-imidazol-2-yl)prop-2-enoic acid 12e containing a c(5)O spacer exhibits a pIC(50) value of 5.13 +/- 0.04 at mGAT3, but is devoid of significant selectivity for this GABA transporter. However, the inhibitory potency displayed by 12e at mGAT3 nominally surpasses that of SNAP-5294 reported as the most potent inhibitor of mGAT3 so far. (C) 2016 Elsevier SAS. All rights reserved.