title: Atropisomeric quinazolin-4-one derivatives are potent noncompetitive alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonists.
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.
authors.affiliation: Global Research and Development, Groton Laboratories, Pfizer Inc., CT 06340, USA.
authors.forename: W M
authors.initials: WM
authors.lastname: Welch
authors.forename: F E
authors.initials: FE
authors.lastname: Ewing
authors.forename: J
authors.initials: J
authors.lastname: Huang
authors.forename: F S
authors.initials: FS
authors.lastname: Menniti
authors.forename: M J
authors.initials: MJ
authors.lastname: Pagnozzi
authors.forename: K
authors.initials: K
authors.lastname: Kelly
authors.forename: P A
authors.initials: PA
authors.lastname: Seymour
authors.forename: V
authors.initials: V
authors.lastname: Guanowsky
authors.forename: S
authors.initials: S
authors.lastname: Guhan
authors.forename: M R
authors.initials: MR
authors.lastname: Guinn
authors.forename: D
authors.initials: D
authors.lastname: Critchett
authors.forename: J
authors.initials: J
authors.lastname: Lazzaro
authors.forename: A H
authors.initials: AH
authors.lastname: Ganong
authors.forename: K M
authors.initials: KM
authors.lastname: DeVries
authors.forename: T L
authors.initials: TL
authors.lastname: Staigers
authors.forename: B L
authors.initials: BL
authors.lastname: Chenard
mesh_terms: 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
chemical_list: D000927:Anticonvulsants; D009466:Neuromuscular Blocking Agents; D011725:Pyridines; D011799:Quinazolines; D052999:Quinazolinones; D018091:Receptors, AMPA; C005718:piriqualone; D002118:Calcium