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).,ACS Chemical Neuroscience

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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).
ACS Chemical Neuroscience ( IF 4.1 ) Pub Date : 2019-10-01 , DOI: 10.1021/acschemneuro.9b00447
Peng Wu ₁ , Walden E Bjørn-Yoshimoto ₁ , Markus Staudt ₁ , Anders A Jensen ₁ , Lennart Bunch ₁

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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).

中文翻译：

咪唑并[1,2-a]吡啶-3-胺作为兴奋性氨基酸转运蛋白亚型3（EAAT3）的第一选择抑制剂的鉴定与构效关系研究。

在本研究中，在兴奋性氨基酸转运子亚型3（EAAT3）上筛选了49,087个化合物的文库，从而鉴定出2-（呋喃-2-基）-8-甲基-N-（邻甲苯基）咪唑并[1,2一]吡啶-3-胺（3A），其显示出对抑制EAAT3（IC的> 20倍偏好₅₀ = 13μM）以上EAAT1,2,4（EAAT1：IC ₅₀〜250微米; EAAT2 ，4：IC ₅₀ > 250μM）。结果表明，在7位和/或8位上有一个小的亲脂性取代基（甲基或溴）对于活性至关重要。此外，邻甲苯基的取代方式（化合物5b）和2-位取代基的化学性质（化合物7b）对于EAAT3相对于EAAT1,2的选择性至关重要。最突出的类似物来本研究出来是图3a和3e中的显示为EAAT3〜35倍的选择性（IC ₅₀ = 7.2μM）以上EAAT1,2,4（IC ₅₀〜250微米）。

更新日期：2019-10-02

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