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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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