jm301268u_si_001.pdf (152.11 kB)
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
journal contribution
posted on 2012-12-13, 00:00 authored by Shigeki Hibi, Koshi Ueno, Satoshi Nagato, Koki Kawano, Koichi Ito, Yoshihiko Norimine, Osamu Takenaka, Takahisa Hanada, Masahiro YonagaDysfunction 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.