Quinazolin-4-one alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonists: structure-activity relationship of the C-2 side chain tether.
A series of 6-fluoro-3-(2-chlorophenyl)quinazolin-4-ones has been prepared, which contains a 2-fluorophenyl ring attached to C-2 by a variety of two-atom tethers. These compounds were used to probe the structure-activity relationship (SAR) for AMPA receptor inhibition. The relative potencies of the new compounds ranged from 11 nM to greater than 10 microM. The differential activity of the compounds was rationalized on the basis of alterations of the 2-fluorophenyl positioning (planar and radial) relative to the quinazolin-4-one ring based on computational methods. From this effort, new AMPA receptor antagonists, containing the methylamino tether group, have been identified.
Chenard
B L
BL
Global Research and Development, Groton Laboratories, Pfizer Inc., Groton, Connecticut 06340, USA. chenardbl@groton.pfizer.com
Welch
W M
WM
Blake
J F
JF
Butler
T W
TW
Reinhold
A
A
Ewing
F E
FE
Menniti
F S
FS
Pagnozzi
M J
MJ
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology / Q000378:metabolism; D018691:Excitatory Amino Acid Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D011799:Quinazolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D018691:Excitatory Amino Acid Antagonists; D011799:Quinazolines; D018091:Receptors, AMPA; D002118:Calcium