Atropisomeric quinazolin-4-one derivatives are potent noncompetitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonists

被引:135
作者
Welch, WM [1 ]
Ewing, FE [1 ]
Huang, J [1 ]
Menniti, FS [1 ]
Pagnozzi, MJ [1 ]
Kelly, K [1 ]
Seymour, PA [1 ]
Guanowsky, V [1 ]
Guhan, S [1 ]
Guinn, MR [1 ]
Critchett, D [1 ]
Lazzaro, J [1 ]
Ganong, AH [1 ]
DeVries, KM [1 ]
Staigers, TL [1 ]
Chenard, BL [1 ]
机构
[1] Pfizer Inc, Groton Labs, Global Res & Dev, Groton, CT 06340 USA
关键词
D O I
10.1016/S0960-894X(00)00622-3
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
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. (C) 2001 Elsevier Science Ltd. All rights reserved.
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收藏
页码:177 / 181
页数:5
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