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

2001; Elsevier BV; Volume: 11; Issue: 2 Linguagem: Inglês

10.1016/s0960-894x(00)00622-3

1464-3405

W. M. WELCH, Frank E. Ewing, J. HUANG, Frank S. Menniti, Martin J. Pagnozzi, Kristin N. Kelly, P A Seymour, Victor Guanowsky, Sam Guhan, Mark Guinn, D.J. Critchett, John T. Lazzaro, Alan H. Ganong, Keith M. DeVries, Thomas Staigers, B. L. CHENARD,

Synthesis of heterocyclic compounds

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.