3.2.2 Lead Compound Identification by SerendipityMany of the significant advances in drug discovery over the past one and a half centuries
owe their success to serendipity; the discovery of penicillin (discussed in chapter 9) is
a legendary example of its importance. However, many other drugs were also discovered
by accident. Continuing the theme of epilepsy from section 3.2.1 provides additional
examples of serendipity and drug discovery.
3.2.2.1 The Benzodiazepines: Diazepam and Serendipity
The benzodiazepines are one of the most widely used (and abused) classes of drugs; they
are widely used in the treatment of epilepsy, insomnia, anxiety, movement disorders, and
a variety of other neurological disorders. The discovery of the benzodiazepines is a good
example of the importance of serendipity.
In the early 1950s, following the accidental discovery of phenothiazines as antipsy-
chotic agents, interest in tricyclic molecules as potential therapeutic agents for neurolog-
ical and psychiatric disorders became widespread. Accordingly, in 1954, Sternbach of
Hoffmann–La Roche laboratories decided to reinvestigate the synthetic chemistry of a
series of tricyclic benzheptoxdiazine compounds upon which he had worked more than
twenty years earlier. By reacting an alkyl halide with a variety of secondary amines, he
prepared forty analogs, all of which were inactive as muscle relaxants and sedatives.
When additional chemical studies revealed that these compounds were really quinazoline-
3-oxides rather than benzheptoxdiazines, the project was summarily abandoned in 1955.
Nearly two years later, a colleague at Hoffmann–La Roche discovered an untested
crystalline sample while cleaning and tidying cluttered laboratory benches. Although
many other compounds had been simply discarded, this compound, later called chlor-
diazepoxide, was submitted for biological evaluation. Chlordiazepoxide (7-chloro-
2-(methylamino)-5-phenyl-3H-1,4-benzodiazepine-4-oxide; Librium) demonstrated
profound anti-anxiety properties. Additional chemical studies revealed that this single
compound was a 1,4-benzodiazepine, unlike its forty quinazoline-3-oxide predecessors—
the chance use of methylamine, a primary rather than a secondary amine, had resulted
in a different synthetic pathway. Numerous analogs, including diazepam (Valium), were
soon prepared and the anticonvulsant properties of this class of compounds were
quickly discerned. The benzodiazepines soon emerged as one of the most important,
and lucrative, classes of drug molecules.
The discovery of benzodiazepines is a story of serendipity and certainly one that is
difficult to predictably reproduce as part of a drug discovery program. Regrettably (or
fortuitously), this story of the benzodiazepines is not an isolated example. Valproic acid,
an agent used to treat epilepsy, migraine, chronic pain, and bipolar affective disorder,
was also discovered by accident.
3.2.2.2 Aliphatic Carboxylates: Valproic Acid and Serendipity
In postwar France, the Berthier Pharmaceutical Company in Grenoble began to pursue a
sideline project of producing soothing liquid bismuth preparations for acute tonsillitis.
Being dissatisfied with the commonly used oils, they elected to use the supposedly
DESIGNING DRUG MOLECULES TO FIT RECEPTORS 111