James Whyte Black
James Whyte Black. Courtesy Albert and Mary Lasker Foundation.
James Whyte Black (1924–2010) was among the first of the “rational design” school of drug discoverers (see George Hitchings and Gertrude Elion) to use the concept of physiological receptors rigorously. According to the receptor concept, there are special receptors for each of the body’s chemical messengers that trigger important physiological changes throughout the body. Using this concept, Black discovered a new class of cardiovascular drugs, the beta-blockers, and a class of antiulcer medicines, the histamine-2 (H2)-blockers.
Black was the fourth of five sons of a mining engineer and colliery manager in Fife, Scotland. He described himself as coasting through most of his school years, daydreaming except during two periods of intense study—music between the ages of 12 and 14 and mathematics between the ages of 14 and 16. He was, however, able to win a competitive scholarship to St. Andrews University. Under the influence of an older brother who had also attended St. Andrews, he chose to study medicine and, after graduating, joined the physiology department there as an assistant lecturer. In 1947 he took a teaching position in a medical school in Singapore to earn money to repay the debts incurred by his medical education. Returning to England in 1950, he was asked to start a new physiology department at the University of Glasgow Veterinary School, where he built up a research laboratory equipped with the most advanced cardiovascular technology he could obtain.
In Glasgow he and his colleagues made preliminary investigations into the two areas in which Black would make his most significant contributions: regulating the histamine-stimulated secretion of gastric acid that causes peptic ulcers, and rectifying the decreased oxygen supply to the heart in patients with narrowed coronary arteries, which can cause angina (chest pain) or, worse, heart attack. Their initial research into the latter was aimed at increasing the oxygen supply to the heart, but it occurred to Black that there might be another way to remedy the oxygen insufficiency. Instead of increasing the oxygen supply, why not reduce the heart’s demand for oxygen?
Black thought that intervening in hormonal activity might provide the control he was seeking. In the 1940s research had been conducted on the functions of adrenaline. This hormone exhibited puzzling, nearly contradictory, effects on various organs in the body, including the heart. In 1948 Raymond Ahlquist of the Medical College of Georgia in the United States suggested that such organs possessed two sets of receptors, which he designated alpha and beta, that mediated the action of adrenaline, thus explaining how the same hormone could have quite distinct effects. The alpha-receptors of the heart, for example, use adrenaline to contract the muscle; the beta-receptors relax the muscle but increase the heart rate.
In 1956 Black set out to look for a specific adrenaline antagonist, that is, a substance that would inhibit the heart rate–increasing action of adrenaline, which produced a high demand for oxygen, by blocking the beta receptors. He first sought help from Imperial Chemical Industries (ICI) Pharmaceuticals Division (now AstraZeneca), and he later joined their new Alderley Park laboratories near Manchester.
Meanwhile, at Eli Lilly and Company in Indianapolis, scientists looking for a new bronchodilator to use in asthmatic patients synthesized dichloroisoproterenol (DCI). In the course of their testing they noted that adrenaline, long known as a bronchodilator, had no dilating effect on tracheal strips that had previously been exposed to DCI; that is to say, DCI antagonized adrenaline. Two scientists at Emory University in Atlanta then tested DCI’s effect on the heart. They found that the drug also inhibited the changes in heart rate and muscle tension produced by adrenaline, seeming to block the beta-receptors of Ahlquist’s theory. DCI, however, displayed considerable adrenaline-like activity—a fact that slowed Lilly’s own development of DCI as a heart medicine.
After some initial hesitation, in early 1960 Black and his colleagues at ICI took DCI as their most promising compound on which to perform structural modifications. The chemists went to work on developing new molecules, one of which was propranolol. This new drug proved effective at relieving anginal pain and at regulating some irregularities in patients’ heartbeats and displayed no adverse effects. ICI brought propranolol to market in 1964 as the first widely used beta-blocker. One of the scientists who worked on the clinical development of beta-blockers discovered that drugs of this class could be used to treat other heart conditions and also reduced high blood pressure—a use for which they are commonly prescribed today.
In 1963, while propranolol was still being launched, Black left ICI for Smith, Kline and French Laboratories (now GlaxoSmithKline) in Welwyn Garden City near London. He was eager to start a new research program, believing that the antihistamines of the day that were used to treat allergies (see Daniel Bovet) were analogous to the alpha-receptor antagonists in the cardiovascular system and that the equivalent of a beta-receptor antagonist was needed to block, for example, histamine-stimulated acid secretion in the stomach.
Black and his associates set about creating chemical analogues of histamine and testing them in vitro and in vivo. In their first breakthrough they made a molecule that stimulated acid secretion without causing the other histamine responses, thus implying that there is indeed a second receptor, which they labeled H2. Finding an H2 antagonist proved difficult. By 1968, with more than 200 compounds synthesized, they had not yet discovered an H2-blocker. Eventually, after developing more sensitive procedures, they noticed that a compound that they had earlier synthesized with a long side chain based on guanidine, a nitrogen-containing compound, now displayed some slight antagonist activity. They then took this compound as their lead and extended its side chain, overcoming many chemical difficulties in the process, and created burimamide (1972).
Since burimamide was not active when taken orally, the team continued their work, changing the compound’s electronic properties by introducing new groups and a sulfur atom in the midst of the side chain. The result, metiamide, was active orally and was 10 times more potent than burimamide. Because burimamide and metiamide both contained the potentially toxic thiourea group in the side chain, the chemists, now led by Black’s colleague Robin Ganellin, continued their syntheses. They then produced cimetidine, which contains a cyano-guanidine group instead. Meanwhile, of 700 patients treated, a few taking metiamide developed a reversible blood disorder; so all further development focused on cimetidine. In 1976 in the United Kingdom and in 1977 in the United States, it was launched as Tagamet (derived from anTAGonist and ciMETidine) and was enthusiastically received. It and similar drugs developed by other companies, like Glaxo’s Zantac, transformed the lives of ulcer patients around the world.
In 1973, during the final phases of the development of cimetidine, Black took up the chair of pharmacology at University College, London. Four years later he moved to the Wellcome Research Laboratories as director of their therapeutic research division, and from 1984 to 1993 he served as professor of analytical pharmacology at Kings College, London. In 1981, seven years before he received his Nobel Prize in physiology or medicine, he was knighted by Queen Elizabeth II.