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Review
. 2006 Jun;69(3):273-94.
doi: 10.1016/j.eplepsyres.2006.02.004. Epub 2006 Apr 18.

Diverse mechanisms of antiepileptic drugs in the development pipeline

Michael A Rogawski  1
Affiliations
Review

Diverse mechanisms of antiepileptic drugs in the development pipeline

Michael A Rogawski. Epilepsy Res. 2006 Jun.

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 cell-based 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; various selective partial benzodiazepine receptor agonists, including ELB139, which is a positive allosteric modulator of alpha3-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.

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Figures

Fig. 1
Fig. 1
Structures of levetiracetam and two 4-substituted analogs with 10-fold greater SV2A binding activity.
Fig. 2
Fig. 2
Structures of valproate and several valproate-like agents. See text for key to abbreviations. Asymmetric centers are indicated by asterisks.
Fig. 3
Fig. 3
Structures of dicarbamates felbamate and fluorofelbamate and the monocarbamate RWJ-333369.
Fig. 4
Fig. 4
Converging metabolic pathways for carbamazepine, oxcarbazepine and S-licarbazepine acetate (BIA 2-093); the latter two compounds lead to the production licarbazepine, an active anticonvulsant.
Fig. 5
Fig. 5
Classical benzodiazepines with full agonist activity at the benzodiazepine recognition site of GABAA receptors and non-benzodiazepine ligands of the benzodiazepine recognition site with partial agonist activity. TPA023 and ELB139 are highly subunit-selective.
Fig. 6
Fig. 6
General functionalized amino acid structure, with two examples—N-acetyl-DL-alanine-N-benzylamide, the first compound in the class to be identified with anticonvulsant properties, and lacosamide, which is currently in clinical development. The asymmetric center is indicated by an asterisk.
Fig. 7
Fig. 7
Structures of the 2,3-benzodiazepines noncompetitive AMPA receptor antagonists GYKI 52466 and talampanel and the competitive AMPA receptor antagonist NS1209. The asterisk indicates an asymmetric center. Enantiomers of NS1209 have similar properties to the racemate.
Fig. 8
Fig. 8
Structure of the neuroactive steroid ganaxolone.
Fig. 9
Fig. 9
Structures of rufinamide and lamotrigine showing the nitrogen-containing aromatic rings.
Fig. 10
Fig. 10
Structure of retigabine.
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