Medicinal Chemistry, Tsukuba Research Laboratories, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba-shi, Ibaraki 300-2635, Japan.
J Med Chem. 2012 Dec 13;55(23):10584-600. doi: 10.1021/jm301268u. Epub 2012 Dec 4.
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.
谷氨酸能神经传递功能障碍与癫痫和许多其他神经疾病的发病机制有关。在这里，我们描述了一系列 1,3,5-三芳基-1H-吡啶-2-酮衍生物的发现，这些化合物是 AMPA 型离子型谷氨酸受体的非竞争性拮抗剂。通过操纵位于吡啶酮环的 1、3 和 5 位的单个芳环，研究了该系列化合物的构效关系。这最终发现了 2-(2-氧代-1-苯基-5-吡啶-2-基-1,2-二氢吡啶-3-基)苯甲腈（吡仑帕奈，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 Ca2+内流测定（IC50=60 nM）和体内 AMPA 诱导的癫痫发作模型（最低有效剂量为 2 mg/kg po）中均表现出很强的活性。吡仑帕奈目前正在监管审查中，用于与癫痫相关的部分发作性癫痫。
