Identification of a New Class of Selective Excitatory Amino Acid Transporter Subtype 1 (EAAT1) Inhibitors Followed by a Structure-Activity-Relationship Study
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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. / Hansen, Stinne Wessel; Erichsen, Mette Norman; Fu, Bingru; Bjørn-Yoshimoto, Walden Emil; Abrahamsen, Bjarke; Hansen, Jacob Christian; Jensen, Anders A.; Bunch, Lennart.
I: Journal of Medicinal Chemistry, Bind 59, Nr. 19, 2016, s. 8757-8770.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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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
Y1 - 2016
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
VL - 59
SP - 8757
EP - 8770
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 19
ER -
ID: 165167584