Chemical properties of antiepileptic drugs (AEDs)

Between 1990 and 2011 the following fifteen new antiepileptic drugs (AEDs) were approved: eslicarbazepine acetate, felbamate, gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, retigabine, rufinamide, stiripentol, tiagabine, topiramate, vigabatrin, and zonisamide. These AEDs (except felbamate) offer appreciable advantages in terms of their favorable pharmacokinetics, improved tolerability and lower potential for drug interactions. All AEDs introduced after 1990 that are not second generation drugs (with the exception of vigabatrin and tiagabine) were developed empirically (sometimes serendipitously) utilizing mechanism-unbiased anticonvulsant animal models. The empirical nature of the discovery of new AEDs in the last three decades coupled with their multiple mechanisms of action explains their diverse chemical structures. The availability of old and new AEDs with various activity spectra and different tolerability profiles enables clinicians to better tailor drug choice to the characteristics of individual patients. With fifteen new AEDs having entered the market in the past 20years the antiepileptic market is crowded. Consequently, epilepsy alone is not attractive in 2011 to the pharmaceutical industry even though the clinical need of refractory epilepsy remains unmet. Due to this situation, future design of new AEDs must also have a potential in non-epileptic CNS disorders such as neuropathic pain, migraine prophylaxis and bipolar disorder or fibromyalgia as demonstrated by the sales revenues of pregabalin, topiramate and valproic acid. This review analyzes the effect that the emerging knowledge on the chemical properties of the old AEDs starting from phenobarbital (1912) has had on the design of subsequent AEDs and new therapeutics as well as the current approach to AED discovery.