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).
ACS Chem Neurosci
; 10(10): 4414-4429, 2019 10 16.
Article
en En
| MEDLINE
| ID: mdl-31573179
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 â¼ 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 â¼35-fold selectivity for EAAT3 (IC50 = 7.2 µM) over EAAT1,2,4 (IC50 â¼ 250 µM).
Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Piridinas
/
Transportador 3 de Aminoácidos Excitadores
Tipo de estudio:
Diagnostic_studies
Límite:
Humans
Idioma:
En
Año:
2019
Tipo del documento:
Article