β-Indolyloxy Functionalized Aspartate Analogs as Inhibitors of the Excitatory Amino Acid Transporters (EAATs),ACS Medicinal Chemistry Letters

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β-Indolyloxy Functionalized Aspartate Analogs as Inhibitors of the Excitatory Amino Acid Transporters (EAATs)
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2020-09-01 , DOI: 10.1021/acsmedchemlett.0c00342
Na Liu ₁ , Anders A Jensen ₁ , Lennart Bunch ₁

Affiliation

The excitatory amino acid transporters (EAATs) mediate uptake of the major excitatory neurotransmitter l-glutamate (Glu). The essential functions governed by these transporters in regulating the central Glu level make them interesting therapeutic targets in a wide range of neurodegenerative and psychiatric disorders. l-Aspartate (Asp), another EAAT substrate, has served as a privileged scaffold for the development of EAAT inhibitors. In this study, we designed and synthesized the first β-indolyloxy Asp analogs 15a–d with the aim to probe a hitherto unexplored adjacent pocket to the substrate binding site. The pharmacological properties of 15a–d were characterized at hEAAT1-3 and rEAAT4 in a conventional [³H]-d-Asp uptake assay. Notably, thiophene analog 15b and the para-trifluoromethyl phenyl analog 15d were found to be hEAAT1,2-preferring inhibitors exhibiting IC₅₀ values in the high nanomolar range (0.21–0.71 μM) at these two transporters versus IC₅₀ values in the low micromolar range at EAAT3,4 (1.6–8.9 μM). In summary, the results presented herein open up for further structure–activity relationship studies of this new scaffold.

中文翻译：

β-吲哚氧基官能化天冬氨酸类似物作为兴奋性氨基酸转运蛋白 (EAAT) 的抑制剂

兴奋性氨基酸转运蛋白 (EAAT) 介导主要兴奋性神经递质l-谷氨酸 (Glu) 的摄取。这些转运蛋白在调节中枢 Glu 水平方面的基本功能使它们成为广泛的神经退行性疾病和精神疾病的有趣治疗靶点。l -天冬氨酸 (Asp) 是另一种 EAAT 底物，已作为开发 EAAT 抑制剂的特殊支架。在这项研究中，我们设计并合成了第一个 β-吲哚氧基 Asp 类似物15a – d，目的是探测一个迄今为止尚未探索的与底物结合位点相邻的口袋。15a - d的药理特性在常规[ ³ H] -d- Asp 摄取测定中在hEAAT1-3 和rEAAT4 处表征。值得注意的是，噻吩类似物15B和对三氟甲基苯基模拟15D被发现被hEAAT1,2-宁愿抑制剂表现出的IC _50个在这两个转运值在高纳摩尔范围内（0.21-0.71μM）对IC _50个在低微摩尔值EAAT3,4 (1.6–8.9 μM) 的范围。总之，本文提出的结果为进一步研究这种新支架的构效关系开辟了道路。

更新日期：2020-09-01

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