A novel class of AMPA receptor allosteric modulators. Part 1: design, synthesis, and SAR of 3-aryl-4-cyano-5-substituted-heteroaryl-2-carboxylic acid derivatives.
The synthesis and initial SAR studies of novel, highly potent positive allosteric modulators of AMPA receptors based on 3-(4-tert-butylphenyl)-4-cyano-5-methylsulfanyl-thiophene-2-carboxylic acid (6a) are described. SAR studies at the thioether moiety indicated that substitution at this position was mandatory and better potency was achieved with small groups.
Fernandez
Maria-Carmen
MC
Lilly S.A., Avenida de la Industria, 30, 28108 Alcobendas, Madrid, Spain. fernandez_maria-carmen@lilly.com
Castaño
Ana
A
Dominguez
Esteban
E
Escribano
Ana
A
Jiang
Delu
D
Jimenez
Alma
A
Hong
Eric
E
Hornback
William J
WJ
Nisenbaum
Eric S
ES
Rankl
Nancy
N
Tromiczak
Eric
E
Vaught
Grant
G
Zarrinmayeh
Hamideh
H
Zimmerman
Dennis M
DM
D000494:Allosteric Regulation; D002264:Carboxylic Acids; D015195:Drug Design; D018683:Excitatory Amino Acid Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D006571:Heterocyclic Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D018091:Receptors, AMPA / Q000187:drug effects*; D013329:Structure-Activity Relationship; D013440:Sulfides
D002264:Carboxylic Acids; D018683:Excitatory Amino Acid Agents; D006571:Heterocyclic Compounds; D018091:Receptors, AMPA; D013440:Sulfides