Identification and Structure–Activity Relationship Study of Imidazo[1,2-<i>a</i>]pyridine-3-amines as First Selective Inhibitors of Excitatory Amino Acid Transporter Subtype 3 (EAAT3)

Abstract

In the present study, screening of a library of 49,087 compounds at the excitatory amino acid transporter subtype 3 (EAAT3) led to the identification of 2-(furan-2-yl)-8-methyl-<i>N</i>-(<i>o</i>-tolyl)imidazo[1,2-<i>a</i>]pyridin-3-amine (<b>3a</b>) which showed a >20-fold preference for inhibition of EAAT3 (IC₅₀ = 13 μM) over EAAT1,2,4 (EAAT1: IC₅₀ ∼ 250 μM; EAAT2,4: IC₅₀ > 250 μM). It was shown that a small lipophilic substituent (methyl or bromine) at the 7- and/or 8-position was essential for activity. Furthermore, the substitution pattern of the <i>o</i>-tolyl group (compound <b>5b</b>) and the chemical nature of the substituent in the 2-position (compound <b>7b</b>) were shown to be essential for the selectivity toward EAAT3 over EAAT1,2. The most prominent analogues to come out of this study are <b>3a</b> and <b>3e</b> that display ∼35-fold selectivity for EAAT3 (IC₅₀ = 7.2 μM) over EAAT1,2,4 (IC₅₀ ∼ 250 μM).