RESUMO
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.
Assuntos
Descoberta de Drogas , Piridonas/química , Piridonas/farmacologia , Receptores de AMPA/antagonistas & inibidores , Animais , Disponibilidade Biológica , Meia-Vida , Ensaios de Triagem em Larga Escala , Técnicas In Vitro , Espectroscopia de Ressonância Magnética , Masculino , Camundongos , Nitrilas , Piridonas/farmacocinética , Ratos , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Verapamil/análogos & derivados , Verapamil/síntese química , Catálise , Química Orgânica/métodos , Cromatografia Líquida de Alta Pressão , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Compostos Organometálicos/química , Estereoisomerismo , Verapamil/químicaRESUMO
A series of novel neuronal voltage-dependent calcium channel (VDCC) blockers, with inhibitory activity at low micromolar and moderate solubility in water, was discovered by constructing and screening a focused library based on emopamil (1) left hand (ELH) as a bioactive template.