Atropisomeric quinazolin-4-one derivatives are potent noncompetitive alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonists.
Piriqualone (1) was found to be an antagonist of AMPA receptors. Structure activity optimization was conducted on each of the three rings in 1 to afford a series of potent and selective antagonists. The sterically crowded environment surrounding the N-3 aryl group provided sufficient thermal stability for atropisomers to be isolated. Separation of these atropisomers resulted in the identification of (+)-38 (CP-465,022), a compound that binds to the AMPA receptor with high affinity (IC50 = 36 nM) and displays potent anticonvulsant activity.
Welch
W M
WM
Global Research and Development, Groton Laboratories, Pfizer Inc., CT 06340, USA.
Ewing
F E
FE
Huang
J
J
Menniti
F S
FS
Pagnozzi
M J
MJ
Kelly
K
K
Seymour
P A
PA
Guanowsky
V
V
Guhan
S
S
Guinn
M R
MR
Critchett
D
D
Lazzaro
J
J
Ganong
A H
AH
DeVries
K M
KM
Staigers
T L
TL
Chenard
B L
BL
D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism / Q000502:physiology; D002118:Calcium / Q000493:pharmacokinetics; D004195:Disease Models, Animal; D020128:Inhibitory Concentration 50; D007536:Isomerism; D009466:Neuromuscular Blocking Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding; D011725:Pyridines; D011799:Quinazolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D052999:Quinazolinones; D051381:Rats; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors*; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy; D012995:Solubility; D013329:Structure-Activity Relationship; D009435:Synaptic Transmission / Q000187:drug effects
D000927:Anticonvulsants; D009466:Neuromuscular Blocking Agents; D011725:Pyridines; D011799:Quinazolines; D052999:Quinazolinones; D018091:Receptors, AMPA; C005718:piriqualone; D002118:Calcium