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.

中文翻译：

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发现2-（2-氧代-1-苯基-5-吡啶-2--2-基-1,2-二氢吡啶-3-基）苄腈（Perampanel）：一种新型的非竞争性α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）受体拮抗剂

谷氨酸能神经传递功能障碍与癫痫和许多其他神经系统疾病的发病机理有关。在这里，我们描述了一系列1,3,5-三芳基-1 H-吡啶-2-酮衍生物作为AMPA型离子型谷氨酸受体的非竞争性拮抗剂的发现。通过处理位于吡啶酮环的位置1、3和5的单个芳环，研究了该系列化合物的结构-活性关系。最终发现了2-（2-氧代-1-苯基-5-吡啶-2--2-基-1,2-二氢吡啶-3-基）苄腈（perampanel，6），这是一种新型的非竞争性AMPA受体拮抗剂，在体外AMPA诱导的Ca ^2+内流试验中显示出强效活性（IC ₅₀= 60 nM）和体内AMPA诱发的癫痫发作模型（最小有效剂量2 mg / kg po）。目前，Perampanel正在就与癫痫相关的部分发作性癫痫发作进行监管。