Medicinal Chemistry

physiologically inert valproic acid as a solvent for their bismuth compounds. In doing so,
they gained immense practical experience with the handling and manipulation of this
solvent.
In 1962, Pierre Eymard, a graduate student at the University of Lyon, synthesized a
series of khellin derivatives. Khellin is a biologically active substance that occurs in the
fruit of the wild Arabian Khellplant and which has been used for centuries by herbal-
ists for the treatment of kidney stones. Eymard arranged to have his new compounds
biologically evaluated at the École de Médecine et de Pharmacie in nearby Grenoble.
When attempts to produce a solution of these khellin compounds failed, advice was
sought from H. Meunier of the nearby Laboratoire Berthier. In view of Berthier’s recent
peripheral interest in valproic acid as a solvent for bismuth compounds, Meunier
recommended valproic acid as a nontoxic inert solvent.
Eymard’s khellin derivatives were dissolved in valproic acid and, following the practice
of submitting all such compounds for evaluation in an antiepileptic screening model,
they were studied for anticonvulsant activity. These preliminary studies revealed pro-
found anticonvulsant activity. Shortly after this, Meunier serendipitously decided to use
valproic acid as a solvent for an unrelated coumarin compound and, although chemi-
cally dissimilar to Eymard’s khellins, this coumarin exhibited identical anticonvulsant
properties. The fact that both compounds had been dissolved in the same solvent was
realized immediately. The antiepileptic action of valproic acid was thus discovered
completely by accident, with the first successful clinical trial occurring in 1963.
Although serendipity has been quite successful in drug design, it is a method that
is difficult to reproduce. Accordingly, over the past fifty years, a variety of other drug
discovery methods have been pioneered.

3.2.3 Lead Compound Identification from Endogenous Sources

In the attempt to identify logical or rational methods for designing and discovering lead
compounds, the notion of exploiting endogenous molecules quickly comes to mind.
Human disease arises from perturbations of normal biochemical processes. A logical
therapeutic approach involves the administration of one or more of these naturally
occurring endogenous biochemical molecules, or analogs thereof. In addition, certain
human diseases seem to arise from a deficiency of a certain endogenous molecule. It is
reasonable to assume that such diseases could be cured or at least helped by the admin-
istration of the missing molecule.
Medicinal chemistry has many examples of the development of successful thera-
peutics based on an exploration of endogenous compounds. The treatment of diabetes
mellitus, for example, is based upon the administration of insulin, the hormone that
is functionally deficient in this disease. The current treatment of Parkinson’s disease
is based upon the observation that the symptoms of Parkinson’s disease arise from a
deficiency of dopamine, an endogenous molecule within the human brain. Since
dopamine cannot be given as a drug since it fails to cross the blood–brain barrier and
enter the brain, its biosynthetic precursor, L-DOPA, has been successfully developed
as an anti-Parkinson’s drug. Analogously, the symptoms of Alzheimer’s disease arise
from a relative deficiency of acetylcholine within the brain. Current therapies for
Alzheimer’s-type dementia are based upon the administration of cholinesterase

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