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 HibiShigeki UenoKoshi NagatoSatoshi KawanoKoki ItoKoichi NorimineYoshihiko TakenakaOsamu HanadaTakahisa YonagaMasahiro 2012 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-1<i>H</i>-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, <b>6</b>), a novel, noncompetitive AMPA receptor antagonist that showed potent activity in an in vitro AMPA-induced Ca<sup>2+</sup> influx assay (IC<sub>50</sub> = 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.