Identification and Structure-Activity Relationship Study of Imidazo[1,2- a]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-N-(o-tolyl)imidazo[1,2-a]pyridin-3-amine (3a) 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 o-tolyl group (compound 5b) and the chemical nature of the substituent in the 2-position (compound 7b) were shown to be essential for the selectivity toward EAAT3 over EAAT1,2. The most prominent analogues to come out of this study are 3a and 3e that display ∼35-fold selectivity for EAAT3 (IC₅₀ = 7.2 μM) over EAAT1,2,4 (IC₅₀ ∼ 250 μM).

Keywords: EAAT3; EAAT3 inhibitors; Glutamate; excitatory amino acid transporter.