10.1021/jm301268u.s001
Shigeki Hibi
Shigeki
Hibi
Koshi Ueno
Koshi
Ueno
Satoshi Nagato
Satoshi
Nagato
Koki Kawano
Koki
Kawano
Koichi Ito
Koichi
Ito
Yoshihiko Norimine
Yoshihiko
Norimine
Osamu Takenaka
Osamu
Takenaka
Takahisa Hanada
Takahisa
Hanada
Masahiro Yonaga
Masahiro
Yonaga
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
American Chemical Society
2012
series
epilepsy
seizure
IC 50
60 nM
AMPA receptor antagonist
Perampanel
Receptor AntagonistDysfunction
pyridone ring
glutamatergic neurotransmission
2012-12-13 00:00:00
Journal contribution
https://acs.figshare.com/articles/journal_contribution/Discovery_of_2_2_Oxo_1_phenyl_5_pyridin_2_yl_1_2_dihydropyridin_3_yl_benzonitrile_Perampanel_A_Novel_Noncompetitive_Amino_3_hydroxy_5_methyl_4_isoxazolepropanoic_Acid_AMPA_Receptor_Antagonist/2460199
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.