facetious. As mentioned, screening of compounds has a long and rather illustrious
history and has produced many useful anticancer and antibiotic drugs. The discovery of
the anticonvulsant drug phenytoin provides an early example of drug discovery through
screening.
3.2.6.1 Drug Discovery by Screening: Diphenylhydantoin, An Early Example
As a chemical species, the hydantoins have been known since the 1860s. By the latter
half of the nineteenth century numerous hydantoin analogs had been synthesized, but
only one, 5-ethyl-5-phenylhydantoin (nirvanol), demonstrated any clinical utility.
Wernecke introduced nirvanol in 1916 as a “less toxic hypnotic”; however, enthusiasm
rapidly waned when its chronic toxicity became recognized. Not surprisingly, a second
hydantoin, 5,5-diphenylhydantoin (phenytoin), which had long remained on the labora-
tory shelf, appeared doomed to obscurity; phenytoin had been first synthesized by Biltz
in 1908, through a condensation of urea with benzil which exploited a pinacolone
rearrangement.
In the late 1930s, T. Putnam initiated a screening programme to search for new anti-
convulsants, using protection against electroshock-induced convulsions as a selection
criterion. A makeshift apparatus to execute these experiments was assembled using a
commutator salvaged from a World War I German aircraft. Having studied the structure
of phenobarbital, Putnam randomly requested a diverse selection of heterocyclic
phenyl-containing compounds from a variety of chemical manufacturers. He also com-
municated with a number of pharmaceutical companies. The Parke-Davis Company
provided nineteen heterocyclic phenyl-substituted compounds that had been deemed
“worthless hypnotics.” Phenytoin was one of these nineteen compounds. Putnam
screened hundreds of compounds but only phenytoin combined high activity with low
toxicity. In 1936, Putnam’s colleague, Houston Merritt, initiated a clinical evaluation of
phenytoin, which soon led to its widespread marketing as an anticonvulsant drug.
The pioneering screening techniques that heralded the discovery of phenytoin pro-
foundly influenced subsequent antiepileptic drug discovery. Hundreds of hydantoin
analogs were synthesized and screened for biological activity; hundreds of other penta-
atomic heterocyclic compounds (e.g., succinimides, oxazolidinediones) were likewise
synthesized and screened for biological activity. Many of these new compounds found
their way into the market place, with varying degrees of therapeutic success.
3.2.6.2 Drug Discovery by Screening: A Modern Definition
Thankfully, the science of drug discovery by screening has advanced since the time of
Merritt and Putnam. Modern drug discovery by screening is more of a systematic tech-
nological tour de force than a hit-or-miss gamble. The reasons for these advances are
obvious. Although rational drug design is elegant, it is also slow and thus time-inefficient.
It takes a long time to identify the proteins that are involved in a disease, then crystallize
them and design drugs to bind to them. Worse, some proteins, especially membrane- bound
proteins, seem to defy crystallization, while some diseases do not even have identifiable
proteins involved in their pathogenesis and etiology. Screening methods attempt to
address all of these deficiencies in drug discovery.
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