Brivaracetam: A Rational Drug Discovery Success Story

M. Senthilraja

Abstract: A large-scale screening effort to optimize binding affinity identified the 4-n-propyl analogue, brivaracetam, as having greater potency and a broadened spectrum of activity in animal seizure models. Recent phase II clinical trials demonstrating that brivaracetam is efficacious and well tolerated in the treatment of partial onset seizures have validated the strategy of the discovery programme. Brivaracetam is among the first clinically effective AEDs to be discovered by optimization of pharmacodynamic activity at a molecular target.
The discovery of drugs useful in the prevention of epileptic seizures has been a triumph for medicinal chemistry and pharmacology. Drug treatments for epilepsy have been available since 1857, when bromides salts were recognized as having antiseizure activity. In the first half of the twentieth century, two drugs-phenobarbital and phenytoin-became available and they revolutionized the care of persons with epilepsy. Phenobarbital was an early success of synthetic organic chemistry and phenytoin demonstrated the utility of animal models for antiepileptic drug (AED) discovery. Between 1946 and 1978, 16 new AEDs were introduced. A second wave of new drug introductions, now numbering 10, began in 1993 and is currently underway. Most of these new drugs have unique pharmacodynamic properties and they have provided improvements in safety, tolerability and pharmacokinetics, although there is little evidence that they are more efficacious at reducing seizure frequency than older drugs or that they allow previously refractory patients to achieve seizure freedom. observed, 'Nearly all the great discoveries in chemotherapy have been made as a result of a false hypothesis or due to a so-called chance observation.' Indeed, serendipity has played a key role in the discovery of most of the new AEDs, but a critical element has been the availability of predictive animal models. The molecular targets of the AEDs discovered by empirical screening-to the extent that they are known-were usually identified years after the drug had reached the market. For only two marketed agents (tiagabine and vigabatrin) can it be reasonably argued that the drugs were discovered because a specific molecular target was considered.
Brivaracetam, an AED currently in late stage clinical development, represents an unusual success of rational drug discovery, in that the discovery process began with a specific molecular target. However, like most other AEDs, brivaracetam exists because of false hypotheses and chance observations. In the early 1960s, in a search for new sedative hypnotic agents, several cyclic GABA analogues were synthesized based on -butyrolactam (2-oxopyrrolidine). The view was that these agents would calm the brain by interacting with GABA systems. However, instead of being tranquilizers, some of these analogues, including the 2-acetamide piracetam, were found to improve memory in rodents. The mechanism of this effect is still unclear, but it is certainly not related to GABA. In any case, piracetam is prescribed in the belief that it has beneficial effects on memory and cognitive function. Studies in animal models have demonstrated that piracetam has weak anticonvulsant actions, but the drug is not used clinically for the treatment of epilepsy, although it is approved in some markets for myoclonus.


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