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.
An asymmetric synthesis of (2S)-2-(2-isopropyl)-5-hydroxy-2-phenylpentanenitrile (emopamil left hand, 2) has been completed by use of the MAD (methyl aluminum bis(4-methyl-2,6-di-tert-butylphenoxide)-induced rearrangement of a chiral epoxyalcohol as the key reaction. The stereochemistry of the chiral quaternary center was confirmed by transformation of 2 to (S)-noremopamil. This method requires minimal purification procedures and affords high chemical and optical yields. Acid-catalyzed isomerization of an allylaldehyde and retro-aldol type racemization at the quaternary carbon of a nitrile-alcohol were encountered.
Synthesis of 1-Formyl-1,2-dihydroquinoline Derivatives by a Lewis Acid-Catalyzed Cyclization of o-(1-Hydroxy-2-alkenyl)phenyl Isocyanides. -A convenient and efficient method is presented for the synthesis of the title quinoline derivatives (V) based on the BF3 catalyzed cyclization of isocyanides (IV). The present method has the advantages of simple manipulations and the ready availability of starting compounds. -(KOBAYASHI, K.; NAGATO, S.; KAWAKITA, M.; MORIKAWA, O.; KONISHI, H.; Chem. Lett. (1995) 7, 575-576; Dep. Mater. Sci., Fac. Eng., Tottori Univ., Koyama, Tottori 680, Japan; EN)
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