New and Emerging Antiepileptic Drugs

Abstract

This article provides the biologist, chemist, and clinician with an overview into currently existing epilepsy medicines, an appreciation of those currently in development, and a glimpse at future possibilities. The discovery and development of antiepileptic drugs with improved efficacy and side‐effect dimensions are urgently needed. We discuss various strategies for discovering new antiepileptic drugs. We then provide summary data on the mechanisms of action, efficacy, and tolerability of some of the newer third‐generation antiepileptic drugs – eslicarbazepine, brivaracetam, retigabine, lacosamide, and perampanel. Additional compounds that are currently in development for epilepsy are also reviewed. These include the novel α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA) receptor antagonists CERC‐611 and JNJ‐55511118 that are first‐in‐class drugs blocking only those AMPA receptors associated with the auxiliary protein TAPP γ‐8. The GABA A (α2/3)‐selective compounds, KRM‐II‐81, MP‐III‐080, and PF‐06372865 hold additional promise and potential advantage over nonselective GABA A receptor modulators. The developmental status of another positive allosteric modulator of GABA A receptors, the neuroactive steroid ganaxolone, is also summarized. In addition, two mGlu2 receptor modulators, JNJ‐40411813 and LY2812223 are discussed. Finally, initial data on cannabidiol, anakinra, and padsevonil are reviewed. Literature data derived from studies on both human epileptic tissue and rodent seizure modeling were utilized to glean several compelling novel drug targets for consideration in future antiepileptic drug discovery programs. Thus, in the past decade, key advances have been made that are benefiting the epileptic patient community. The current compounds in development and new drug targets give additional promise of improved antiepileptic drugs.

New Imidazodiazepine Analogue, 5-(8-Bromo-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,5-a][1,4]diazepin-3-yl)oxazole, Provides a Simplified Synthetic Scheme, High Oral Plasma and Brain Exposures, and Produces Antiseizure Efficacy in Mice, and Antiepileptogenic Activity in Neural Networks in Brain Slices from a Patient with Mesial Temporal Lobe Epilepsy

“…As KRM-II-81 ( 1 ) (Figure ) moves into development for pharmacoresistant epilepsy and other neurological and psychiatric disorders, − medicinal chemistry has been synthesizing new compounds that could serve as structural backups. A few structural analogues have already been constructed and characterized.…”