James Black dies at 85; Nobel laureate developed Inderal and Tagamet

Dr. James Black, a Scottish Nobel laureate who pioneered the rational design of drugs and, in the process, developed the first widely used drugs for treating heart disease and blocking stomach acid production, died Monday. He was 85. His death was confirmed by the University of Dundee, which did not release details about the cause or place of death.

Black developed propanolol (brand-named Inderal), the first member of the class of drugs known as beta blockers, which revolutionized the care of heart disease. He then developed cimetidine (brand-named Tagamet), which did the same for heartburn and acid reflux. Both are still among the most widely prescribed drugs on Earth, and their discovery, experts said, brought more relief to humans than could an army of doctors in clinical practice.

The drugs did not bring Black financial riches but, in addition to the Nobel, they earned him a knighthood and appointment to the Order of Merit, the highest honor the British sovereign can bestow. The Order of Merit is given to only 24 living people at any time. He was the first Scotsman to receive the honor.

When Black began his research in the 1950s, the development of new drugs was a hit-and-miss proposition. Most existing drugs had been isolated from plants thought to have medicinal properties or by chemically modifying existing drugs and sending large numbers of such compounds through massive screening programs.

His work was based on the inspiration of American scientist Raymond Ahlqvist, who in 1948 discovered that the contraction and relaxation of muscle tissue, including that of the heart, were regulated by separate receptors, which he called alpha and beta.

Existing drugs for the heart were thought to increase the oxygen supply to the organ. Black reasoned that it should be possible to reduce the heart’s need for oxygen by blocking the beta receptors so that the heart did not work as hard. Modeling his potential drugs after chemicals known to bind to the beta receptor, his team in 1962 developed a drug called pronethalol that relaxed the heart. But trials shown that it occasionally produced severe side effects and it was abandoned.

Two years later, the team developed propanolol, which achieved Black’s goals. Clinical trials showed that the drug was useful in the treatment of angina pectoris, tachycardia and tachyarrhythmia. The drug was also found to be effective in the treatment of high blood pressure and to reduce deaths associated with heart attacks.

Black then turned to the study of histamines, which play a role in the immune system and regulation of physiological activity in the gut. Existing antihistamines were only partially successful and Black reasoned, in analogy with muscle tissues, that there were two histamine receptors, which he labeled H1 and H2. Existing antihistamines affected only the first receptor.

In the same approach he had used for propanolol, Black’s team began searching for drugs that would block the H2 receptor. The first drug they found, metiamide, worked, but, like pronethalol, produced unacceptable side effects. But in 1975, they discovered cimetidine, which had a marked effect on peptic ulcer and few side effects.

Tagamet was wildly successful, becoming the first drug to have more than $1 billion per year in sales.

In 1988, Black shared the Nobel Prize in Physiology or Medicine with American researchers Gertrude Elion and George Hitchings, who used a similar targeted approach to develop new drugs to treat cancer.

James Whyte Black was born June 14, 1924 in the Glasgow suburb of Uddington -- in his own words, “a country boy from the coal fields of Fife.” The prototypical brilliant child who was not challenged by schoolwork, he “coasted” through his education in a ramshackle schoolhouse that had to be propped up with timbers to keep it from falling into a mine.

One of his teachers there, however, convinced him to sit for the entrance examination to St. Andrews University at the age of 15, and he was awarded a scholarship to the prestigious school. He chose medicine as a career because he had been intrigued by the textbooks of his older brother William, who had graduated from St. Andrews earlier.

At an undergraduate ball in 1944, he met his future wife, Hilary Vaughan. They were married upon his graduation in 1946 and remained together until her death in 1986.

When Hilary completed her degree in biochemistry in 1947, the couple were burdened with debt and he could not find a job in the U.K., so he took a position at the King Edward VII College of Medicine in Singapore.

Three years later, the couple returned to London with “no home, no income of any kind and no prospects whatsoever.” While knocking on doors searching for a job, a chance encounter with a former professor led him to the University of Glasgow Veterinary School, where he established the department of physiology. During his eight years there, he said, he learned how to be an experimenter.

Formulating his ideas about beta receptors, he approached Imperial Chemical Industries for funding. They suggested, instead, that he join their research laboratories. He did, and the discovery of Inderal made ICI a major player in the international pharmaceutical industry.

Fearing he would be sucked into promotional activities for Inderal rather than being able to develop his ideas about histamines, he left ICI in 1964 to join Smith, Kline & French Laboratories, where he was given free rein to pursue his ideas and he developed cimetidine.

Eventually yearning for a return to academia, he joined University College London in 1973, then the Wellcome Foundation in 1978. In 1984, returned to University College London, then became chancellor of the University of Dundee in 1992.

Black is survived by his second wife, Rona Mackie, whom he married in 1994, and a daughter, Stephanie.

thomas.maugh@latimes.com