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This column traces the modern history of benzodiazepine discovery to illustrate the arduous nature of the process.
By Dilip Ramchandani, M.D.
The development of the benzodiazepines was a landmark in modern psychopharmacology. Their discovery, however, was not accidental. Beginning at the turn of the century, the pharmaceutical industry, quite aware that there was profit to be made, had focused its efforts on the rapid development of "mood-altering" chemicals. The bromides and chloral hydrate had replaced the wonder drug of the 18th century, opium, on the grounds that it was too addictive. They were in turn replaced by the "safer" barbiturates in the 1930s. By the 1950s, however, the addictive potential of barbiturates was causing consternation. The advent of phenothiazines and meprobamate sought to satisfy the increasing need for less addictive prescriptions to treat anxiety. Despite their tremendous success, it was apparent that the phenothiazines had too many side effects to warrant their uninhibited use in ambulatory patients, and meprobamate was often too weak. So the need for a drug with a mid-range potency between meprobamate and phenothiazines was great.
In 1954, therefore, in the New Jersey-based laboratories of Hoffmann-La Roche, Dr. Leo Sternbach began to study a class of unexplored compounds, the hepto-xdiazines, with which he had previously worked as a postdoctoral student in Poland. A chemist usually chooses one of several routes to seek new therapeutic agents, such as synthesizing drugs similar to naturally occurring medicinal products or modifying existing drugs to find compounds with greater usefulness. Another option is to develop a theory and apply compounds to test it or randomly screen chemicals for pharmacologically active and therapeutic effects.
Dr. Sternbach decided to revisit compounds he had helped synthesize 20 years earlier but whose biological activity was unknown. He soon discovered that these compounds were not seven-membered rings as he had previously believed but were six-membered rings. Although he was able to derive 40 new compounds from them, all, unfortunately, proved pharmacologically inert. Finally, he decided to treat one of the derivatives with methylamine, a primary amine, and labeled the resulting white, crystalline water-soluble powder Ro 5-0690 but shelved it for later examination.
He forgot the compound until a year and a half later, when, during a laboratory cleanup in 1957, he found and submitted it for further evaluation to the pharmacologic research laboratory at Roche. In July of that year he received a report from the pharmacologist, Dr. Lowell Randall, stating that "the substance has hypnotic, sedative, and antistrychnine effects in mice similar to meprobamate." It was also far more potent than meprobamate as a muscle relaxant in cats. Unlike the 40 inert quinazoline 3-oxide compounds that preceded it, this chemical, chlordiazepoxide, proved to be a 1,4-benzodiazepine with a seven-membered ring structure and great clinical potential.
Time was now ripe for clinical trials after more detailed pharmacological and toxicity studies had been performed. In 1958 the compound was administered to geriatric patients in relatively large doses and found to be primarily sedating. It also produced ataxia and slurred speech. As a result, interest in the drug diminished until Dr. Irvin Cohen in Galveston, Tex., and two other clinical investigators agreed to participate in clinical trials of the drug in their psychoneurotic patients who received office-based treatment. All three were impressed with the drug's anxiolytic action, which occurred without any accompanying clouding of consciousness or intellectual dysfunction. Toxicity was minimal, and the success of Phase III testing in thousands of patients in three settings (prison, clinic, and private office) led to its approval by the FDA in February 1960. A month later, it was marketed as Librium. The first clinical note on its therapeutic efficacy was published in the March 1960 issue of the Journal of the American Medical Association.
In 1963 Valium was introduced as a more potent tranquilizer. The third benzodiazepine, Serax, was introduced in June 1965. Despite the initial abandonment of chlordiazepoxide as a mere sedative, it became apparent, with persistent investigation, that drugs of its class reduced anxiety, complications of acute alcoholism, convulsive states, and muscular tension. Their use became universal, and newer varieties of benzodiazepines proliferated. At last count, there were 39 benzodiazepines available for a variety of clinical uses.
Dr. Ramchandani is the editor of the History Notes column.