A novel class of positive allosteric modulators of AMPA receptors: design, synthesis, and structure-activity relationships of 3-biphenyl-4-yl-4-cyano-5-ethyl-1-methyl-1H-pyrrole-2-carboxylic acid, LY2059346.
The synthesis and structure-activity relationship (SAR) of novel and highly potent positive allosteric modulators of AMPA receptors, 3-biphenyl-4-yl-4-cyano-5-ethyl-1-methyl-1H-pyrrole-2-carboxylic acid, are described. These studies indicated that higher potency was achieved with ortho substitution of the distal (D) phenyl of the 3-biphenyl ring and resulted in the discovery of a potent pyrrole LY2059346 (23q), that was selected for further evaluation in in vitro native tissue assays and in vivo experiments.
Zarrinmayeh
Hamideh
H
Eli Lilly and Co, Lilly Research Laboratories, Indianapolis, IN 46285, USA. Zarrinmayeh_Hamideh@lilly.com
Tromiczak
Eric
E
Zimmerman
Dennis M
DM
Rankl
Nancy
N
Ho
Ken H
KH
Dominguez
Esteban
E
Castaño
Ana
A
Escribano
Ana
A
Fernandez
Carmen
C
Jimenez
Alma
A
Hornback
William J
WJ
Nisenbaum
Eric S
ES
D000494:Allosteric Regulation; D002264:Carboxylic Acids / Q000138:chemical synthesis / Q000494:pharmacology; D002460:Cell Line; D015195:Drug Design; D018846:Excitatory Amino Acids / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism; D006801:Humans; D011758:Pyrroles / Q000138:chemical synthesis* / Q000494:pharmacology*; D018091:Receptors, AMPA / Q000819:agonists*; D013329:Structure-Activity Relationship; D014162:Transfection
D002264:Carboxylic Acids; D018846:Excitatory Amino Acids; D011758:Pyrroles; D018091:Receptors, AMPA; D018698:Glutamic Acid