Atropisomeric quinazolin-4-one derivatives are potent noncompetitive alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonists |
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| Authors: | Welch W M Ewing F E Huang J Menniti F S Pagnozzi M J Kelly K Seymour P A Guanowsky V Guhan S Guinn M R Critchett D Lazzaro J Ganong A H DeVries K M Staigers T L Chenard B L |
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| Institution: | Global Research and Development, Groton Laboratories, Pfizer Inc., CT 06340, USA. |
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| Abstract: | 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. |
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