Perampanel: A Novel, Noncompetitive AMPA Receptor Antagonist for the Treatment of Epilepsy

Quinoxalinedione derivatives, were the first selective α-amino-3-hydroxy-5- methyl-4-isoxazolepropionic acid (AMPA) receptor antagonists to be identified, and these were found to compete with glutamate for its binding site on the AMPA receptors with high affinity. Continued research identified the potential of targeting neuronal AMPA-type glutamate receptors, which have a key role in mediating fast excitatory neurotransmission. This chapter describes a series of 1,3,5-triaryl-1H-pyridine-2-one derivatives as novel and noncompetitive antagonists of AMPA-type iGluRs and gives an account of how they were developed for the treatment of epilepsy, a process finally resulting in the discovery of perampanel. Perampanel, which has been developed through a process of systematic optimization following high throughput screening (HTS), exhibited extremely potent in vitroand in vivoeffects. The discovery of perampanel and its progression through Phases I to III of clinical development have validated the clinical utility of an orally active, highly selective, noncompetitive AMPA receptor antagonist.