Identification of a New Class of Selective Excitatory Amino Acid Transporter Subtype 1 (EAAT1) Inhibitors Followed by a Structure-Activity-Relationship Study

Stinne Wessel Hansen; Mette Norman Erichsen; Bingru Fu; Walden Emil Bjørn-Yoshimoto; Bjarke Abrahamsen; Jacob Christian Hansen; Anders A. Jensen; Lennart Bunch

doi:10.1021/acs.jmedchem.6b01058

Identification of a New Class of Selective Excitatory Amino Acid Transporter Subtype 1 (EAAT1) Inhibitors Followed by a Structure-Activity-Relationship Study

Stinne Wessel Hansen, Mette Norman Erichsen, Bingru Fu, Walden Emil Bjørn-Yoshimoto, Bjarke Abrahamsen, Jacob Christian Hansen, Anders A. Jensen, Lennart Bunch

10 Citations (Scopus)

Abstract

Screening of a small compound library at the three excitatory amino acid transporter subtypes 1–3 (EAAT1–3) resulted in the identification of compound (Z)-4-chloro-3-(5-((3-(2-ethoxy-2-oxoethyl)-2,4-dioxothiazolidin-5-ylidene)methyl)furan-2-yl)benzoic acid (1a) that exhibited a distinct preference as an inhibitor at EAAT1 (IC50 20 μM) compared to EAAT2 and EAAT3 (IC50 > 300 μM). This prompted us to subject 1a to an elaborate structure–activity relationship study through the purchase and synthesis and subsequent pharmacological characterization of a total of 36 analogues. Although this effort did not result in analogues with substantially improved inhibitory potencies at EAAT1 compared to that displayed by the hit, it provided a detailed insight into structural requirements for EAAT1 activity of this scaffold. The discovery of this new class of EAAT1-selective inhibitors not only supplements the currently available pharmacological tools in the EAAT field but also substantiates the notion that EAAT ligands not derived from α-amino acids hold considerable potential in terms of subtype-selective modulation of the transporters.

Original language	English
Journal	Journal of Medicinal Chemistry
Volume	59
Issue number	19
Pages (from-to)	8757-8770
Number of pages	14
ISSN	0022-2623
DOIs	https://doi.org/10.1021/acs.jmedchem.6b01058
Publication status	Published - 13 Oct 2016

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Hansen, S. W., Erichsen, M. N., Fu, B., Bjørn-Yoshimoto, W. E., Abrahamsen, B., Hansen, J. C., Jensen, A. A., & Bunch, L. (2016). Identification of a New Class of Selective Excitatory Amino Acid Transporter Subtype 1 (EAAT1) Inhibitors Followed by a Structure-Activity-Relationship Study. Journal of Medicinal Chemistry, 59(19), 8757-8770. https://doi.org/10.1021/acs.jmedchem.6b01058

Identification of a New Class of Selective Excitatory Amino Acid Transporter Subtype 1 (EAAT1) Inhibitors Followed by a Structure-Activity-Relationship Study. / Hansen, Stinne Wessel; Erichsen, Mette Norman; Fu, Bingru et al.

In: Journal of Medicinal Chemistry, Vol. 59, No. 19, 13.10.2016, p. 8757-8770.

Research output: Contribution to journal › Journal article › Research › peer-review

Hansen, SW, Erichsen, MN, Fu, B, Bjørn-Yoshimoto, WE, Abrahamsen, B, Hansen, JC, Jensen, AA & Bunch, L 2016, 'Identification of a New Class of Selective Excitatory Amino Acid Transporter Subtype 1 (EAAT1) Inhibitors Followed by a Structure-Activity-Relationship Study', Journal of Medicinal Chemistry, vol. 59, no. 19, pp. 8757-8770. https://doi.org/10.1021/acs.jmedchem.6b01058

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abstract = "Screening of a small compound library at the three excitatory amino acid transporter subtypes 1–3 (EAAT1–3) resulted in the identification of compound (Z)-4-chloro-3-(5-((3-(2-ethoxy-2-oxoethyl)-2,4-dioxothiazolidin-5-ylidene)methyl)furan-2-yl)benzoic acid (1a) that exhibited a distinct preference as an inhibitor at EAAT1 (IC50 20 μM) compared to EAAT2 and EAAT3 (IC50 > 300 μM). This prompted us to subject 1a to an elaborate structure–activity relationship study through the purchase and synthesis and subsequent pharmacological characterization of a total of 36 analogues. Although this effort did not result in analogues with substantially improved inhibitory potencies at EAAT1 compared to that displayed by the hit, it provided a detailed insight into structural requirements for EAAT1 activity of this scaffold. The discovery of this new class of EAAT1-selective inhibitors not only supplements the currently available pharmacological tools in the EAAT field but also substantiates the notion that EAAT ligands not derived from α-amino acids hold considerable potential in terms of subtype-selective modulation of the transporters.",

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AB - Screening of a small compound library at the three excitatory amino acid transporter subtypes 1–3 (EAAT1–3) resulted in the identification of compound (Z)-4-chloro-3-(5-((3-(2-ethoxy-2-oxoethyl)-2,4-dioxothiazolidin-5-ylidene)methyl)furan-2-yl)benzoic acid (1a) that exhibited a distinct preference as an inhibitor at EAAT1 (IC50 20 μM) compared to EAAT2 and EAAT3 (IC50 > 300 μM). This prompted us to subject 1a to an elaborate structure–activity relationship study through the purchase and synthesis and subsequent pharmacological characterization of a total of 36 analogues. Although this effort did not result in analogues with substantially improved inhibitory potencies at EAAT1 compared to that displayed by the hit, it provided a detailed insight into structural requirements for EAAT1 activity of this scaffold. The discovery of this new class of EAAT1-selective inhibitors not only supplements the currently available pharmacological tools in the EAAT field but also substantiates the notion that EAAT ligands not derived from α-amino acids hold considerable potential in terms of subtype-selective modulation of the transporters.

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Identification of a New Class of Selective Excitatory Amino Acid Transporter Subtype 1 (EAAT1) Inhibitors Followed by a Structure-Activity-Relationship Study

Abstract

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