Miguel A. Ondetti
Miguel A. Ondetti working with molecular models of captopril. Courtesy Bristol-Myers Squibb Company.
In the 1970s Miguel A. Ondetti (1930–2004) and his colleagues at the pharmaceutical company E. R. Squibb (now Bristol-Myers Squibb) used the principles of rational drug design pioneered by James Whyte Black, George Hitchings, and Gertrude Elion to develop a new means of treating high blood pressure, or hypertension. The new drugs were called angiotensin-converting enzyme (ACE) inhibitors.
Ondetti began his career in Buenos Aires, Argentina, where he grew up in a family of Italian descent. He and his brother set up a makeshift chemistry laboratory in their home. While attempting to electrolyze copper sulfate, Ondetti suffered a strong electric shock, which put an end to his home experiments. It did not, however, quell his desire to become a chemist. Unfortunately, he had to put his aspirations on hold while he and his brother attended a commercial high school so they could quickly obtain jobs to help support their family.
Once the would-be chemist was secure in his position as a bookkeeper, he applied to the university. He was turned down because he had not taken the required preparatory courses. It was, however, possible to take examinations in the various subjects instead. Ondetti, after studying on his own, took some 30 examinations and was eventually admitted to the University of Buenos Aires. He used to arrive at work in the payroll department of Argentina’s Department of Energy at 7:00 a.m. and leave at 2:00 p.m. in order to attend lectures and laboratories.
By 1955 he had earned a licentiate in chemistry (equivalent to a master’s degree), after which he won a scholarship to work on his doctoral dissertation at the Squibb Institute for Medical Research in Buenos Aires. In the 1950s, E. R. Squibb had been given monopoly rights to manufacture antibiotics in Argentina. In exchange for this privilege, the firm was required to invest some of its profits in the country—hence the institute and Ondetti’s scholarship. (Squibb established its first and main Institute for Medical Research in New Brunswick, New Jersey, in 1938.)
After the scholarship year was over, Ondetti was offered a full-time position with Squibb, which he turned down. Instead, he took a job in development at another chemical company, but that only lasted a week, and he returned to his bookkeeping job. Luckily, Squibb soon had another position open, which Ondetti took in 1957, the same year that he received his Ph.D. from the University of Buenos Aires.
At Squibb, Ondetti worked in the natural-products area, isolating biologically active alkaloids from plant materials. To make ends meet, he taught chemistry in the evenings at his alma mater and at the Catholic Institute for Teachers.
In 1960 Squibb offered Ondetti a position in the United States, at their main laboratories in New Jersey, where the research facilities were superior and the salaries much higher. There he was assigned to a newly formed peptide research group. Peptides are molecules made up of two or more amino acids chained together by a chemical bond called a peptide bond. (Proteins are longer chains of amino acids joined together in this way, and are sometimes referred to as polypeptides.) Peptide research was a new field for Ondetti, but he learned quickly. In fact, he was chosen to replace the group’s leader when the latter left Squibb in 1966.
Among the peptides that Ondetti investigated were insulin, a hormone that regulates glucose in the blood; bradykinin, a substance with several functions in the body, including the dilation of certain blood vessels; secretin, a hormone that stimulates the pancreas to secrete bicarbonate and water, in other words, that acts as a natural antacid; and cholecystolinin, which stimulates the contraction of the gallbladder and the secretion of enzymes from the pancreas. The purpose of the program was to make new drugs out of some of the body’s own peptides. But because most peptides are easily broken down by digestive enzymes, they were only effective in injected form, and efforts to develop them into an orally administered form, preferred by patients, proved persistently difficult.
In 1967 Squibb researchers were asked to focus on developing cardiovascular drugs. By this time a great deal was known about the many factors that contribute to high blood pressure, including the role of renin. This substance is produced in the kidneys and cleaves or splits angiotensinogen, a large protein manufactured in the liver, to produce angiotensin I. In turn, angiotensin I is cleaved by an angiotensin-converting enzyme, which is synthesized mostly in the lungs, to produce angiotensin II. Angiotensin II had been implicated as a cause of constriction of blood vessels, which causes blood pressure to rise. If the angiotensin-converting enzyme—ACE—could be inhibited, some types of hypertension could then be controlled.
In early 1968 Ondetti was invited to attend a meeting with a consultant, John Vane, then with Britain’s Royal College of Surgeons, who was soon to become famous for his explanation of the efficacy of aspirin. Vane reported that recent results from his laboratory seemed to show that peptides from the venom of the Brazilian pit viper could block the conversion of angiotensin I to II and meanwhile activate bradykinin, which allowed the bradykinin to do its work of dilating blood vessels. A bite from the viper caused its victim’s death through a sharp drop in blood pressure, but these same peptides might prove useful in treating hypertension.
Squibb researchers Miguel Ondetti (left) and David W. Cushman. Courtesy Bristol-Myers Squibb Company.
In a project to isolate, characterize, and eventually synthesize these blocking peptides, Ondetti teamed up with David Cushman, a biochemist. Cushman’s job was to develop tests to show the effect on ACE of the substances isolated by Ondetti and his assistants. The most likely candidate to emerge from their work was teprotide, but however hard they tried, Ondetti’s team could not modify the molecule so that it could be taken orally. They then began to screen compounds randomly, looking for evidence of activity against ACE. Two thousand non-peptide compounds later, they were no closer to their goal. Because the research seemed to be at an impasse, in 1973 Squibb’s work on ACE inhibitors officially ended. The peptide-synthesis group was subsumed by a new antibiotics group, which Ondetti headed as a step in his assuming ever-broadening responsibilities in the administration of research at Squibb.
But Ondetti and Cushman remained interested in the subject of ACE inhibitors. In 1974 Cushman noticed a paper by scientists who had found an inhibitor of another enzyme and explained the inhibitor’s success as a function of its structure. These researchers deduced that their enzyme inhibitor combined, in one molecule, certain features of the two products resulting from the action of the enzyme on its normal substrate. Specifically, their inhibitor contained molecular groups similar to those on the fragments of the normal substrate that showed how that substrate had been bound by the enzyme before being split. They had in fact created a false substrate to trick the enzyme. Armed with this rationale, Ondetti and a colleague synthesized an amino acid molecule, succinyl-L-proline, which they thought would be an angiotensin I mimic and effectively tie up ACE. Right off the bat, they had found a weak but specific ACE inhibitor and bradykinin potentiator.
While still officially assigned to other research projects, the investigators from the old team then proceeded to synthesize and test new molecules. But soon they were able to convince their managers that they were engaged in an important project that deserved their undivided attention and the support of other researchers at Squibb. They ultimately produced s-3-mercaptopropanoyl-L-proline, or captopril. It showed ten times more activity in vitro than teprotide, and in vivo was almost as efficacious when given orally as when given intravenously.
Clinical trials of captopril (brand name Capoten) began in 1976. The rapid escalation of the oral dose, the use of the drug in all sorts of complicated cases, and the consequent side effects led the U.S. Food and Drug Administration to restrict its approval in 1982 for use only as a drug of last resort, after alternatives had been exhausted. In 1984, after further clinical trials, approval was extended for use in all degrees of hypertension.
For having discovered this new class of drugs, which were widely imitated by other pharmaceutical companies, Ondetti received many awards in his lifetime, including the Perkin Medal, the highest award in the United States given for innovation in the chemical industry.