Diverse mechanisms of antiepileptic drugs in the development pipeline

Abstract

There is a remarkable array of new chemical entities in the current antiepileptic drug (AED) development pipeline. In some cases, the compounds were synthesized in an attempt improve upon the activity of marketed AEDs. In other cases, the discovery of antiepileptic potential was largely serendipitous. Entry into the pipeline begins with the demonstration of activity in one or more animal screening models. Results from testing in a panel of such models provide a basis to differentiate agents and may offer clues as to the mechanism. Target activity may then be defined through cellbased studies, often years after the initial identification of activity. Some pipeline compounds are believed to act through conventional targets, whereas others are structurally novel and may act by novel mechanisms. Follow-on agents include the levetiracetam analogs brivaracetam and seletracetam that act as SV2A-ligands; the valproate-like agents valrocemide, valnoctamide, propylisopropyl acetamide, and isovaleramide; the felbamate analog flurofelbamate, a dicarbamate, and the unrelated carbamate RWJ-333369; the oxcarbazepine analog licarbazepine, which probably acts as a use-dependent sodium channel blockers, and its prodrug acetate BIA 2-093; and various selective partial benzodiazepine receptor agonists, including ELB139, which is a positive allosteric modulator of α3-containing GABA A receptors. A variety of AEDs that may act through novel targets are also in clinical development: lacosamide, a functionalized amino acid; talampanel, a 2,3-benzodiazepine selective noncompetitive AMPA receptor antagonist; NS1209, a competitive AMPA receptor antagonist; ganaxolone, a neuroactive steroid that acts as a positive modulator of GABA A receptors; retigabine, a KCNQ potassium channel opener with activity as a GABA A receptor positive modulator; the benzanilide KCNQ potassium channel opener ICA-27243 that is more selective than retigabine; and rufinamide, a triazole of unknown mechanism.

Molecular Targets for Antiepileptic Drug Development

“…152,153 Several other classes of compounds have been shown to act as KCNQ2-5 channel openers, including benzamides, benzisoxazoles, and phenylacrylamides. 25,138 Some of these protect against seizures in animal models and are more specific for KCNQ channels than is retigabine, confirming that opening of KCNQ channels per se is an anticonvulsant mechanism.…”

“…However, retigabine and newer KCNQ K ϩ channel openers have anticonvulsant activity in animal models and retigabine has shown clinical efficacy. 25 Finally, many metabolic poisons induce seizures. Studying the pathophysiology of such seizures may be useful to understanding the therapeutic action of the ketogenic diet, which could define an entirely new set of targets for AEDs.…”

“…202,203 At the same time, however, there is also evidence that rodent models do not adequately predict liability for sedation, so that agents demonstrated to be nonsedative in rodents may cause sedation in humans. 25 The emerging understanding of the different roles of phasic and tonic inhibition in epileptic phenomena may suggest improved approaches to targeting GABA A receptors for epilepsy therapy. 204 For example, neuroactive steroids selectively target GABA A receptors containing ␦ subunits that mediate tonic inhibition 205,206 (TABLE 5).…”

“…It has undergone clinical evaluation in humans for the treatment of refractory status epilepticus. 25 Because NS1209 is not orally bioavailable, it is administered intravenously.…”

Valproic Acid: Second Generation

“…Most of them are currently in clinical trials. 1,[4][5][6][7][8] The compounds presented in Table 1 can be divided into two categories: 1) new CNS-active molecules (e.g., lacosamide, retigabine and rufinamide); and 2) derivatives of existing CNS drugs being developed as second generation to existing AEDs, such as carbamazepine, valproic acid (VPA), pregabalin, felbamate, and levetiracetam. While most of the new AEDs were developed empirically, and in many cases serendipitously, the second generation of existing AEDs were designed to widen their CNS activity, as well as to improve their efficacy, safety, tolerability, and pharmacokinetic profile.…”