ABSTRACT
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.
Subject(s)
Drug Discovery , Pyridones/chemistry , Pyridones/pharmacology , Receptors, AMPA/antagonists & inhibitors , Animals , Biological Availability , Half-Life , High-Throughput Screening Assays , In Vitro Techniques , Magnetic Resonance Spectroscopy , Male , Mice , Nitriles , Pyridones/pharmacokinetics , Rats , Structure-Activity RelationshipABSTRACT
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.
Subject(s)
Calcium Channel Blockers/chemistry , Calcium Channel Blockers/pharmacology , Calcium Channels, N-Type/drug effects , Synaptosomes/drug effects , Verapamil/analogs & derivatives , Verapamil/chemistry , Animals , Combinatorial Chemistry Techniques , Ion Channel Gating/drug effects , Piperazines/chemistry , Rats , Solubility , Stereoisomerism , Structure-Activity Relationship , Synaptosomes/metabolismABSTRACT
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.
