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)

Peng Wu; Walden E Bjørn-Yoshimoto; Markus Staudt; Anders A Jensen; Lennart Bunch

doi:10.1021/acschemneuro.9b00447

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)

Peng Wu, Walden E Bjørn-Yoshimoto, Markus Staudt, Anders A Jensen, Lennart Bunch

3 Citationer (Scopus)

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).

Originalsprog	Engelsk
Tidsskrift	ACS Chemical Neuroscience
Vol/bind	10
Sider (fra-til)	4414-4429
ISSN	1948-7193
DOI	https://doi.org/10.1021/acschemneuro.9b00447
Status	Udgivet - 16 okt. 2019

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10.1021/acschemneuro.9b00447

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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). / Wu, Peng; Bjørn-Yoshimoto, Walden E ; Staudt, Markus et al.

I: ACS Chemical Neuroscience, Bind 10, 16.10.2019, s. 4414-4429.

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

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title = "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).",

author = "Peng Wu and Bj{\o}rn-Yoshimoto, {Walden E} and Markus Staudt and Jensen, {Anders A} and Lennart Bunch",

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doi = "10.1021/acschemneuro.9b00447",

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AU - Wu, Peng

AU - Bjørn-Yoshimoto, Walden E

AU - Staudt, Markus

AU - Jensen, Anders A

AU - Bunch, Lennart

PY - 2019/10/16

Y1 - 2019/10/16

N2 - 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).

AB - 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).

U2 - 10.1021/acschemneuro.9b00447

DO - 10.1021/acschemneuro.9b00447

M3 - Journal article

C2 - 31573179

SN - 1948-7193

VL - 10

SP - 4414

EP - 4429

JO - ACS Chemical Neuroscience

JF - ACS Chemical Neuroscience

ER -

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

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