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 Citationer (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.

Originalsprog	Engelsk
Tidsskrift	Journal of Medicinal Chemistry
Vol/bind	59
Udgave nummer	19
Sider (fra-til)	8757-8770
Antal sider	14
ISSN	0022-2623
DOI	https://doi.org/10.1021/acs.jmedchem.6b01058
Status	Udgivet - 13 okt. 2016

Adgang til dokumentet

10.1021/acs.jmedchem.6b01058

Citationsformater

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.

I: Journal of Medicinal Chemistry, Bind 59, Nr. 19, 13.10.2016, s. 8757-8770.

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › 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, bind 59, nr. 19, s. 8757-8770. https://doi.org/10.1021/acs.jmedchem.6b01058

@article{0ac1b4d8bff2417fba1dc32e752aceb3,

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

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.",

author = "Hansen, {Stinne Wessel} and Erichsen, {Mette Norman} and Bingru Fu and Bj{\o}rn-Yoshimoto, {Walden Emil} and Bjarke Abrahamsen and Hansen, {Jacob Christian} and Jensen, {Anders A.} and Lennart Bunch",

year = "2016",

month = oct,

day = "13",

doi = "10.1021/acs.jmedchem.6b01058",

language = "English",

volume = "59",

pages = "8757--8770",

journal = "Journal of Medicinal Chemistry",

issn = "0022-2623",

publisher = "American Chemical Society",

number = "19",

}

TY - JOUR

T1 - Identification of a New Class of Selective Excitatory Amino Acid Transporter Subtype 1 (EAAT1) Inhibitors Followed by a Structure-Activity-Relationship Study

AU - Hansen, Stinne Wessel

AU - Erichsen, Mette Norman

AU - Fu, Bingru

AU - Bjørn-Yoshimoto, Walden Emil

AU - Abrahamsen, Bjarke

AU - Hansen, Jacob Christian

AU - Jensen, Anders A.

AU - Bunch, Lennart

PY - 2016/10/13

Y1 - 2016/10/13

N2 - 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.

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.

U2 - 10.1021/acs.jmedchem.6b01058

DO - 10.1021/acs.jmedchem.6b01058

M3 - Journal article

C2 - 27626828

SN - 0022-2623

VL - 59

SP - 8757

EP - 8770

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 19

ER -

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

Abstract

Adgang til dokumentet

Fingeraftryk

Citationsformater