Synthesis and biological evaluation of a series of N-alkylated imidazole alkanoic acids as mGAT3 selective GABA uptake inhibitors

Add time:08/02/2019    Source:sciencedirect.com

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-methoxyphenyl)-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 C5O spacer exhibits a pIC50 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.

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