title: Discovery of 2-(2-oxo-1-phenyl-5-pyridin-2-yl-1,2-dihydropyridin-3-yl)benzonitrile (perampanel): a novel, noncompetitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropanoic acid (AMPA) receptor antagonist.
abstract: Dysfunction of glutamatergic neurotransmission has been implicated in the pathogenesis of epilepsy and numerous other neurological diseases. Here we describe the discovery of a series of 1,3,5-triaryl-1H-pyridin-2-one derivatives as noncompetitive antagonists of AMPA-type ionotropic glutamate receptors. The structure-activity relationships for this series of compounds were investigated by manipulating individual aromatic rings located at positions 1, 3, and 5 of the pyridone ring. This culminated in the discovery of 2-(2-oxo-1-phenyl-5-pyridin-2-yl-1,2-dihydropyridin-3-yl)benzonitrile (perampanel, 6), a novel, noncompetitive AMPA receptor antagonist that showed potent activity in an in vitro AMPA-induced Ca2+ influx assay (IC50=60 nM) and in an in vivo AMPA-induced seizure model (minimum effective dose of 2 mg/kg po). Perampanel is currently in regulatory submission for partial-onset seizures associated with epilepsy.
authors.affiliation: Medicinal Chemistry, Tsukuba Research Laboratories, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba-shi, Ibaraki 300-2635, Japan. s-hibi@hhc.eisai.co.jp
authors.forename: Shigeki
authors.initials: S
authors.lastname: Hibi
authors.forename: Koshi
authors.initials: K
authors.lastname: Ueno
authors.forename: Satoshi
authors.initials: S
authors.lastname: Nagato
authors.forename: Koki
authors.initials: K
authors.lastname: Kawano
authors.forename: Koichi
authors.initials: K
authors.lastname: Ito
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Norimine
authors.forename: Osamu
authors.initials: O
authors.lastname: Takenaka
authors.forename: Takahisa
authors.initials: T
authors.lastname: Hanada
authors.forename: Masahiro
authors.initials: M
authors.lastname: Yonaga
mesh_terms: D000818:Animals; D001682:Biological Availability; D055808:Drug Discovery; D006207:Half-Life; D057166:High-Throughput Screening Assays; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D009570:Nitriles; D011728:Pyridones / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D009570:Nitriles; D011728:Pyridones; D018091:Receptors, AMPA; C551441:perampanel