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

• Published in: Journal of medicinal chemistry Vol. 59; no. 19; pp. 8757 - 8770
• Main Authors: Hansen, Stinne W, Erichsen, Mette N, Fu, Bingru, Bjørn-Yoshimoto, Walden E, Abrahamsen, Bjarke, Hansen, Jacob C, Jensen, Anders A, Bunch, Lennart
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 13.10.2016; Amer Chemical Soc
• Subjects: Benzoates - chemistry; Benzoates - pharmacology; Chemistry, Medicinal; Excitatory Amino Acid Transporter 1 - antagonists & inhibitors; Excitatory Amino Acid Transporter 1 - metabolism; Furans - chemistry; Furans - pharmacology; Halogenation; HEK293 Cells; Humans; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Science & Technology; Structure-Activity Relationship; Thiazolidines - chemistry; Thiazolidines - pharmacology; POTENT; ANALOGS; PHARMACOLOGICAL CHARACTERIZATION; MECHANISMS; BIOAVAILABILITY; MODULATION; UCPH-101
• ISSN: 0022-2623; 1520-4804; 1520-4804
• DOI: 10.1021/acs.jmedchem.6b01058

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.