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
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
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DOI：
10.1021/jm301268u
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发表时间：
2012-12-13
影响因子：
7.3
通讯作者：
Yonaga, Masahiro
中科院分区：
文献类型：
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作者：
Hibi, Shigeki;Ueno, Koshi;Yonaga, Masahiro
癫痫和许多其他神经系统疾病的发病机制涉及到多巴胺能神经传递功能障碍。在这里，我们描述了一系列的1，3，5-三芳基-1H-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。这一系列化合物的构效关系进行了研究，通过操纵个别的芳香环位于位置1，3，和5的吡啶酮环。最终发现了2-（2-氧代-1-苯基-5-吡啶-2-基-1，2-二氢吡啶-3-基）苯甲腈（perampanel，6），这是一种新型非竞争性AMPA受体拮抗剂，在体外AMPA诱导的Ca 2+内流试验（IC 50 = 60 nM）和体内AMPA诱导的癫痫发作模型（最小有效剂量为2 mg/kg po）中显示出强效活性。Perampanel目前正在提交用于癫痫相关部分性发作的监管申请。
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.