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Discovery of Levetiracetam (Keppra(R)): The first SV2A ligand for the treatment of epilepsy
Published on March 28, 2013 35 min
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My name is Henrik Klitgaard. I am a PhD research fellow within the Neuroscience Therapeutic Area at UCB. The purpose of this presentation is to share with you the drug discovery story of levetiracetam that led to the identification of the first SV2A ligand for the treatment of epilepsy.
Levetiracetam is a pyrrolidine derivative with high solubility and relatively low molecular weight. This chemical structure is novel and different from all other antiepileptic drugs.
The anti-epileptic potential of levetiracetam was originally discovered by random screening showing a potent ability to protect against all phases of seizure activity induced by an acoustic stimulus in sound-sensitive mice. Levetiracetam showed a protective ED_50 value of 17 mg per kilo against clonic convulsions after IP administration. Levetiracetam, the S-enantiomer, remains active after a central injection into the brain, whereas the R-enantiomer and the main metabolite lacks activity in this model, suggesting that the obtained seizure suppression relates to a central action of levetiracetam.
Maximal electroshock seizures, MES seizures, have for several decades been one of the two conventional screening models in the search for new antiepileptic drugs. Later, PTZ seizures also became involved in the search for anticonvulsant drugs. Their most extensive use has probably been in the Antiepileptic Drug Development Program at NIH, in which several thousands of compounds have been screened since 1975 based on the anticonvulsant activity in these two models. The table on this slide illustrates data from these two tests obtained in mice with the classical drugs currently prescribed for the treatment of epilepsy. All these drugs are able to generate an effective dose protecting 50% of the animals, an ED_50 value, either against tonic hindlimb extension in the MES test, or against clonic convulsions in this CD_97 PTZ test. Therefore, it has been assumed that all potential drugs will reveal anticonvulsant activity in at least one of these two tests. Furthermore, the activity profile of these drugs in the two tests or spectrum effect of valproate, selective action of phenytoin and carbamazepine in the MES test and the inverse for ethosuximide together with their established clinical efficacy as nearest the assumption that the MES test predict efficacy against generalized tonic-clonic and partial seizures in men, and that the CD_97 PTZ test predicts efficacy against generalized absence and mild clonal seizures. It was therefore a major complication to the discovery efforts of levetiracetam that the drug was shown to be inactive in both of these tests, as shown on the next slide. This slide contains the same table