1999 Albert Lasker Clinical Medical Research Award

ACE inhibitors for treating hypertension

David Cushman and Miguel Ondetti Like true love, the course of truly pathbreaking biomedical research seldom runs smooth, but persistence and commitment do pay off. The story of the long, productive collaboration between David Cushman, a biochemist, and Miguel Ondetti, a chemist, is a remarkable tale of the ups and down of experimental science which, in this case, ends on a high note with the design of an important new class of drugs for hypertension and congestive heart failure.

Cushman and Ondetti share the 1999 Albert Lasker Award in Clinical Medical Research for the discovery and development of captopril, the first orally active ACE inhibitor—the parent drug to what is today a pharmaceutical treasure trove of newer drugs in cardiovascular medicine.

"It would not be an exaggeration to say that when we started collaborating in the identification of angiotensin converting enzyme (ACE) inhibitors in the late 1960s, we had no idea of the impact that our work would eventually have on the study and management of cardiovascular diseases," said Cushman and Ondetti a decade ago as they reviewed their work.

But it would be misleading to suggest that their accomplishments were the result of serendipity or good luck. In truth, their story is a prescient illustration of "rational drug design," a concept that is much heralded today as something made possible by computer imaging and genome science. But in the late 1960s and early 1970s, when the Cushman-Ondetti story begins, they pursued rational drug design with little more than a clear idea, open minds, and what Cushman calls, "straightforward, simple, chemical thinking."

Cushman and Ondetti have spent their professional lives at what is now the Bristol-Myers Squibb Pharmaceutical Research Institute in New Brunswick and Princeton, New Jersey. In the 1960s, ACE, which forms the hypertensive peptide angiotensin II from an inactive precursor angiotensin I, was recognized as a potential player in blood pressure regulation, but there were no good assays for characterizing either the enzyme or agents that inhibit its capacity to raise blood pressure.

Cushman, who received his PhD from the University of Illinois, Urbana in 1966, joined the Squibb Institute in 1968 where, after unsuccessfully attempting to isolate plant enzymes, he developed the first quantitative assay for ACE and purified and characterized the enzyme.

Ondetti, a 1957 graduate of the University of Buenos Aires School of Sciences, was studying the chemical properties of natural products from plants at a Squibb outpost in Argentina when he was offered a position at the Institute's main laboratory in New Jersey. There, he joined a laboratory devoted to peptide synthesis.

"Because peptides are the natural messengers of the body, peptides were expected to lead to very specific drugs with few side effects," Ondetti observes. "Changes in a single amino acid in a peptide sequence can produce significant changes in a peptide's behavior, showing how finely tuned biological activity can be."

A seminar in 1968 by Sir John Vane, a scientific consultant to Squibb, was the seminal event that led to the Cushman-Ondetti collaboration. Vane, who directed a laboratory at the Royal College of Surgeons in London, reported that peptides extracted from the venom of a Brazilian viper, Bothrops jararaca, by his co-worker, the Brazilian pharmacologist Sergio Ferreira, inhibit ACE, thus preventing formation of the hypertensive peptide angiotensin II. (This might play some role in enhancing the lethal action of the snake's venom, which kills quickly by causing a rapid, catastrophic plunge in blood pressure.)

The challenge to the Squibb researchers was clear: utilize the ACE assay to isolate and determine amino acid sequences of these snake venom peptides with an eye to new drug development.

Within a couple of years Cushman and Ondetti had isolated several peptides including a nine-amino-acid peptide, teprotide. They synthesized teprotide, and with colleagues at Squibb moved quickly into animal trials and then human studies of teprotide as an ACE inhibitor and anti-hypertensive drug.

The project was both a success and a failure. Teprotide was an effective ACE inhibitor, but it also was a large molecule—too large to be absorbed when given orally. Although it did lower blood pressure in hypertensive patients who received the drug by injection, proving once and for all the medical utility of ACE inhibitors, its widespread medical value was plainly limited because it could not be administered orally. Much had been learned, but the project was shelved.

Then, in 1974, Cushman read a paper in the journal Biochemistry that described a new potent and specific inhibitor of carboxypeptidase A, an enzyme that is important in the gastrointestinal system. Cushman and Ondetti immediately saw that it might be possible to design an analogous simple chemical compound that might be a specific inhibitor of ACE, which they felt sure was an enzyme very similar in structure to the much better characterized carboxypeptidase A. Using this new approach as a path back to their own "shelved" research, Cushman and Ondetti began again.

This time they took a different approach that proved essential to their subsequent success. Instead of concentrating on the structure of agents that could inhibit ACE, they directed their attention to the structure of the angiotensin converting enzyme—a structure that was not actually known, but which had been hypothesized on the basis of its probable similarity to carboxypeptidase A.

"Although understanding the relationship between the structure of teprotide and its biological activity was important to the eventual development of captopril, the key point of our new design strategy was the shift in focus from the inhibitor to the enzyme," Cushman and Ondetti observed. They began constructing agents that because of their molecular structures were likely to bind to the active site on ACE in a manner similar to the binding of the potent inhibitor of the analogous enzyme carboxypeptidase A.

Several interactions were proposed between ACE and the new class of inhibitors. The most important turned out to be interaction of a group on the inhibitor with the zinc ion proposed at the active site of ACE. Captopril, the final result of this process, contains a sulfhydryl group properly positioned to interact with the zinc of ACE, thereby guaranteeing the drug's efficacy.

Equally important, captopril is a small, orally active compound, easily absorbed into the bloodstream and therefore an ideal drug. Captopril entered clinical trials in 1977 and was approved by the Food and Drug Administration in 1981.

Although newer drugs have come along, the basic chemistry that led to captopril remains the underpinning of virtually all ACE inhibitors. They are now used not only for patients with hypertension or congestive heart failure but also play a role in treating kidney disease in diabetics and play a protective role in patients with progressive renal failure.

Looking back on the invention of captopril, Cushman and Ondetti draw interesting lessons about success and failure in science. It is obvious that they approached drug design in an entirely "rational" way. They note, "Many other approaches to drug development that appeared equally rational have ended in failure. As chemists and biologists dig deeply into the mechanisms of different diseases, they often follow the approach we used, and they often fail, sometimes because the 'rationale' is wrong and sometimes because they do not pursue it long enough. It has been our good luck to have collaborated on one that worked."

Key Publications of David Cushman

Cushman, D.W., Plusec, J., Williams, H.J., Weaver, E.R., Sabo, E.F., Kocy, O., Cheung, H.S., and Ondetti, M.A. (1973) Inhibition of angiotensin-converting enzyme by analogs of peptides from Bothrops jacaraca venom. Experientia 29: 1032–1035.

Ondetti, M.A., Rubin, B., and Cushman, D.W. (1977) Design of specific inhibitors of angiotensin-converting enzyme: new class of orally active antihypertensive agents. Science 196: 441–444.

Cushman, D.W., Cheung, H.S., Sabo, E.F., Ondetti, M.A. (1978) Design of potent competitive inhibitors of angiotensin-converting enzyme, carboxyalkanoyl and mercaptoalkanoyl amino acids. Biochemistry 16: 5484–5491.

Ondetti, M.A., Condon, M.E., Reid, J., Sabo, E.F. Cheung, H.S., Cushman, D.W. (1979) Design of specific inhibitors of carboxypeptidases. A and B. Biochemistry 18:1427–1430.

Cheung, H.S., Wang, F.L., Ondetti, M.A., Sabo, E.F., and Cushman, D.W. (1980) Binding of peptide substrates and inhibitors of angiotensins-converting enzyme: importance of the carboxyl-terminal dipeptide sequence. J. Biol. Chem. 225: 410–417.

Cushman, D.W. and Ondetti, M.A. History of the design of Captopril and related inhibitors of angiotensin converting enzyme. (1992) Hypertension 17: 589–592.

Key Publications of Miguel Ondetti

Ondetti, M.A., and Thomas, P.L. (1965) Synthesis of a peptide lactone related to vernamycin B. J. Amer. Chem. Soc. 87: 4373.

Ondetti, M.A., Narayanan, V.L., Saltza, M. von, Sheehan, J.T., Sabo, E.F., and Bodansky, M. (1968) The synthesis of secretion. III. The fragment-condensation approach. J. Amer. Chem. Soc. 90: 4711.

Ondetti, M.A., Plusec, J., Sabo, E.F., Sheehan, J.T., and Williams, N. (1970) Synthesis of the cholecystokinin-pancreozymin. I. The C-terminal dodecapeptide. J. Amer. Chem. Soc. 92: 195.

Ondetti, M.A., Williams, N.J., Sabo, E.F., Plusec, J., Weaver, E.R. and Kocy, O. (1971). Angiotensin-converting enzyme inhibitors from the venom of Bothrops jararaca. Isolation elucidation of structure and synthesis.

Ondetti, M.A., Rubin, B., and Cushman, D.W. (1977) Design of specific inhibitors of angiotensin-converting enzyme: new class of orally active antihypertensive agents. J. Antibiotics 30: 765–759.

Ondetti, M.A., Condon, M.E., Reid, J., Sabo, E.F. Cheung, H.S., Cushman, D.W. (1979) Design of specific inhibitors of carboxypeptidases A and B. Biochemistry 18:1427–1430.

David Cushman and Miguel Ondetti

Award presentation by Joseph Goldstein

One hundred years ago, two noteworthy events took place in Stockholm, Sweden. Both had far-reaching effects on the biomedical sciences. One was the settlement of Alfred Nobel's controversial will and the creation of the Nobel Foundation. This event had immediate impact and is well known to all of us. The second Stockholm event, occurring at precisely the same time, involved a remarkable series of experiments that laid the groundwork for this year's Lasker Award in Clinical Research.

In 1896, two physiologists at the Karolinska Institute, Robert Tigerstedt and Per Bergmann, injected extracts of kidneys into the bloodstream of rabbits, and they made a dramatic observation: The extracts produced an acute elevation in the blood pressure. These observations led Tigerstedt and Bergmann to propose that the kidney secretes a hormone with vasopressor properties. They named this hormone renin, befitting its renal origin, and they advanced the concept that renin could form the link between kidney disease and hypertension. The Swedish scientists published their results in 1898 in the Scandinavian Archives of Physiology. But unlike Alfred Nobel's one-page will published in the same year, Tigerstedt and Bergmann's 48-page article had no impact. Like Nobel, it lay buried in Sweden for the next 36 years.

Then, in 1934, Harry Goldblatt, a Cleveland physician, placed a clamp on the artery leading to the kidney of a dog and produced the first animal model of chronic hypertension. Goldblatt proposed that the decrease in blood supply causes the kidney to release a vasopressor substance. Goldblatt was unaware of the earlier discovery of renin. The connection between the Goldblatt kidney and renin was not made until the 1950s when scientists delineated the renin-angiotensin system, which is the major mechanism the body uses to control blood pressure.

When blood volume falls, the kidney releases renin into the bloodstream. Renin is not a true hormone; instead it is a proteolytic enzyme that starts a proteolytic cascade. Renin cleaves a large plasma protein to liberate a small 10-amino acid peptide called angiotensin I. Angiotensin I also does not directly raise the blood pressure. It must first be cleaved by another protease—the angiotensin converting enzyme. Angiotensin converting enzyme, affectionately known as ACE, clips two amino acids from the carboxy-terminal end of angiotensin I to produce an active 8-amino acid peptide called angiotensin II. Angiotensin II is the most potent natural vasopressor made by the body. It raises blood pressure by two actions. First, it constricts blood vessels, narrowing their diameter and raising their resistance. And second, it triggers the release of a steroid hormone called aldosterone, which induces the kidney to retain salt and water, thereby over-filling the circulatory system. In 1958, the Lasker Award in Basic Research was given to Irvine Page of the Cleveland Clinic for his pioneering research in delineating the renin-angiotensin system.

Under ordinary circumstances, the renin-angiotensin system is essential for health. It allows the body to maintain a stable blood pressure under conditions in which blood volume is depleted, such as after vomiting, diarrhea, or vigorous exercise. But in certain individuals, the renin-angiotensin system becomes overactive. It raises blood pressure inappropriately. The high blood pressure damages blood vessels, leading to strokes, heart attacks, heart failure, and kidney failure. Inhibitors of the renin-angiotensin system should be ideal agents to lower blood pressure and prevent the complications of hypertension, but how can we block this complex system? This problem was solved by David Cushman and Miguel Ondetti, the recipients of this year's Lasker Award in Clinical Research.

The story behind their discovery is a fascinating one, full of twists and turns. It begins in the banana plantations of southwestern Brazil where workers in the field would suddenly collapse after being bitten by a pit viper snake called Bothrops jararaca. This collapse was due to a sudden and catastrophic drop in blood pressure. In the late 1960s, scientists working in London in the laboratory of Sir John Vane discovered the reason for the sudden drop in blood pressure: The snake venom contained potent peptide toxins that inhibit ACE, the enzyme that generates angiotensin II. News of this discovery spread around the world, and the race was on to find a safe and orally active ACE inhibitor that would lower blood pressure.

At the Squibb Institute for Medical Research, now Bristol-Myers Squibb, two young scientists—David Cushman, an enzymologist, and Miguel Ondetti, a protein chemist—were assigned to investigate this problem. In 1970, their first step was to purify the molecule in the snake venom that inhibited ACE and then determine its chemical nature. The most potent ACE inhibitor in venom turned out to be a peptide that contained only nine amino acids. The Squibb scientists synthesized this peptide in pure form and provided it to two clinical investigators, Hans Brunner and John Laragh, then at Columbia P&S Medical Center. Brunner and Laragh administered the 9-amino acid ACE inhibitor to hypertensive patients and showed that it was extremely effective in lowering blood pressure. The therapeutic principle was established, but there was one serious problem. The purified peptide did not work orally; the peptide was too large to be absorbed from the gut. It could only work when given by intravenous injection, ruling out its use for the chronic treatment of hypertension.

Cushman and Ondetti set about to convert the 9-amino acid peptide into an oral peptidomimetic drug. Traditional chemical approaches did not work. In the meantime, scientists at Squibb began to screen thousands of chemicals that had been synthesized for other purposes. None of these "off-the-shelf" chemicals inhibited ACE; the mass screening effort was a failure, and the ACE project was terminated. Cushman was shifted to a program in antibiotics and Ondetti to prostaglandins.

But the curious Cushman and the unstoppable Ondetti never lost their fascination with ACE. They continued to discuss ways to develop an oral inhibitor based on the sequence of the snake venom peptide. They had several ACEs up their sleeves. First, they were struck by the resemblance of ACE to a well-studied digestive enzyme called carboxypeptidase A whose atomic structure had been determined by X-ray crystallography several years earlier by William Lipscomb at Harvard. Like carboxypeptidase, ACE cleaves amino acids from the carboxy-terminal end of peptide substrates. Like carboxypeptidase, ACE contains a tightly bound zinc atom in the active site. But there was one fundamental difference between ACE and carboxypeptidase. ACE split off the last two amino acids from the end of its peptide substrate, whereas carboxypeptidase split off only one.

From Lipscomb's atomic structure, Cushman and Ondetti knew how carboxypeptidase split off the last amino acid from the peptide substrate. The substrate bound to the enzyme at a site called the peptide binding site. Immediately next to this site was the zinc atom that interacted with the peptide bond that was to be cleaved. Cushman and Ondetti knew one other crucial fact about carboxypeptidase. This fact they learned on the afternoon of Wednesday, March 13, 1974, when they happened on a year-old research article by Byers and Wolfensen that described a potent inhibitor of carboxypeptidase. This was the epiphanous moment in the discovery of the ACE inhibitors.

The inhibitor that Cushman and Ondetti read about was designed to bind tightly to carboxypeptidase, blocking entry of the normal peptide substrate. As soon as they discussed this paper, Cushman and Ondetti perceived something that other scientists had overlooked: the carboxypeptidase inhibitor worked so well because it contained two functional groups in the same molecule—one of its functional groups mimicked the phenylalanine amino acid to be cleaved, and it bound to the peptide binding site. The other functional group, called the succinyl component, bound to the adjacent zinc atom. That a single inhibitor molecule would bind to two different sites in the same enzyme was quite unusual. Cushman and Ondetti leapt into action: They created a model for the perfect ACE inhibitor based on the carboxypeptidase model.

As their first candidate ACE inhibitor, Cushman and Ondetti chose a modified version of the carboxypeptidase inhibitor in which they changed the phenylalanine amino acid to a proline to mimic the last amino acid in the snake venom peptide that inhibited ACE. This compound showed slight positive activity in their biological assays, indicating that they were on the right track. The breakthrough came 60 compounds later when they replaced the succinyl group with a derivative of cysteine. The sulfhydryl of the cysteine bound zinc much more tightly than the carboxyl of succinyl. Compared with their first compound, the cysteine-proline inhibitor was 30,000-fold more potent. Now remember, Cushman and Ondetti were making all of these molecular manipulations without the benefit of an atomic structure of ACE itself; they were relying on inferences deduced from the X-ray structure of the related carboxypeptidase.

In a final tuning of their cysteine-proline inhibitor, Cushman and Ondetti introduced a methyl group that rendered the drug resistant to attack by peptidases in the stomach and bloodstream. The result was the drug that we now know as captopril—the first orally active ACE inhibitor. As Mae West would say, "The rest is history."

From the moment of conception of their model on March 13, 1974, Cushman and Ondetti took only one and a half years and only 60 synthetic modifications to create captopril. Captopril is a truly amazing achievement: It is a derivative of only two amino acids—one of the simplest, yet one of the most optimized of any drug ever taken by patients. This was the first time that scientists exploited a three-dimensional protein structure to design a drug, ushering in a new technology called "structure-based drug design," which is now used throughout the pharmaceutical industry. The HIV protease inhibitors for AIDS patients were developed via a structure-based approach similar to that pioneered by Cushman and Ondetti. Five new drugs, developed by structure-based design, are currently in clinical trials for treating glaucoma, cancer, psoriasis, thrombosis, and the common cold.

Captopril was approved by the FDA in 1982 for the treatment of hypertension. One year later in 1983, it became the first new drug in 15 years to be approved for the treatment of congestive heart failure. In 1994, captopril won FDA approval as the first drug that prevents kidney disease in patients with diabetes mellitus. In addition to captopril, nine different ACE inhibitors have now been approved for use in patients in the US. Today, ACE inhibitors constitute the major class of drugs used for the treatment of hypertension and its complications.

Hypertension is one of the most common diseases in our society. Fifty million Americans, one of every four adults, have high blood pressure. Antihypertensive drugs are the most frequently prescribed medicines in the US Hypertension is not only common; it is also deadly. Its presence accelerates the atherosclerotic process, producing strokes, heart attacks, heart failure, and kidney disease. Each year hypertension costs this country more than $8 billion in health care expenses and lost productivity. Last year alone, hypertension was responsible for 500,000 deaths in the US. More than half of these deaths occurred in people who either never knew they had hypertension or were never treated effectively.

It's hard to believe that one of these people was the most powerful statesman in the world. Franklin D. Roosevelt was first diagnosed in 1937 with severe hypertension. He was treated with the most potent antihypertensive therapy at the time—bed rest, salt restriction, and phenobarbital. Not surprisingly, his blood pressure did not drop. In 1940, FDR suffered the first of several bouts of heart failure, which were treated with digitalis. His blood pressure continued to rise and at the Yalta Conference in February 1945, he was extremely ill with blood pressures in the range of 250/150. Two months later, FDR died suddenly from a massive cerebral hemorrhage. If ACE inhibitors had been available 40 years earlier, world history might surely have changed.

The good news is that the dread consequences of chronic hypertension are becoming less frequent as more and more people are diagnosed. If hypertension is detected in the early stages, it can now be effectively and safely treated—thanks to this year's Lasker Clinical Awardees, David Cushman and Miguel Ondetti. You've all heard about the "ace in the hole." Well, Cushman and Ondetti discovered the "hole in the ACE" and plugged it with their inhibitor!

David W. Cushman

Nature Medicine Essay

Interview with David Cushman and Leon Rosenberg

Leon Rosenberg, Professor, Department of Molecular Biology and the Woodrow Wilson School of Public and International Affairs, Princeton University, interviews David Cushman, who shares the 1999 Albert Lasker Clinical Medical Research Award with Miguel Ondetti. Dr. Cushman is retired from the Bristol-Myers Squibb Pharmaceutical Research Institute in Princeton, NJ. Dr. Rosenberg is also President and Chief Executive Officer of the Funding First initiative of the Mary Woodard Charitable Trust.

Part 1: Developing Captopril Through 'Pure Chemical Design'
Dr. Cushman says captopril's significance from a basic research point of view is that it was developed through pure chemical design. He credits Dr. John Vane with suggesting angiotensin converting enzyme as a target for research at The Squibb Institute.

Rosenberg: Well Dave, let me start by congratulating you one more time on this marvelous achievement of winning the Lasker Award for Clinical Research. It's a pleasure for me to have the opportunity to interview you in this connection.

Cushman: The pleasure is all mine, sir. I hope my brain is up to this. Six years have passed, and I have been doing a little more reading on what we did in the past, trying to catch up with it all. I hope I'll have something to say for you.

Rosenberg: Dave, were you surprised?

Cushman: Yes, I was surprised. Although I guess I had known a couple of years earlier that we had been nominated. And I wouldn't have expected it would have happened on the first try. So I was more delighted than surprised.

Rosenberg: Let me ask you to tell me what you think is the most important part of the work that you and Miguel and many, many other people did.

Cushman: Okay, I think that's probably two-fold. I've been practicing this because somebody asked me the same question this morning. Well, I think that from a very basic research point of view, the most important aspect was that we actually discovered, probably developed, the first type of drug that was actually developed through pure chemical design. Not discovered in any way by serendipity, but almost every step in the design of the eventual drug was rational and based on chemical principals. And, of course, the obvious other side of this is that this end product that we developed, as we hoped, turned out to be of great medical significance and excited us very much in terms of its ability to help people and to actually pave the way for other developments in the medical community.

Rosenberg: Dave, when you say that the drug--we're talking about captopril, of course--was developed absolutely through rational design, I guess the one place where there had to be some choice made was in the selection of the target. How did that come about?

Cushman: Well, that came about actually as one of many contributions made to my life and to our program at Squibb by Dr. John Vane, who was our consultant...who had just become a consultant, I guess at the Squibb Institute for Medical Research, when Arnold Welch took over as president. John had a lot of good ideas, and he pushed them, and he was also very helpful in my career. But this particular one was that he suggested that somebody at Squibb might be interested in studying a very unusual enzyme with great physiological potential, which was angiotensin converting enzyme. It was unusual as an enzyme, which appealed to me, because its mechanism was different than any other enzyme known at the time in that it knocked off the dipeptide residue from the carboxyl terminal into the peptide substrate--that substrate being angiotensin I, which is an immediate precursor of the potent hypertensive peptide angiotensin II.

And people had been arguing for a long time about the potential of angiotensin II in blood pressure elevation and hypertensive disease and possibly in other areas, too. So it was very exciting. We had here at one time a potential target for drugs in that the enzyme formed a substance, which might be overproduced in hypertension, and, on the other hand, we had a very interesting target from an enzymologist's point of view because it was so unusual and very, very poorly characterized. So it left a lot of room to figure out a way to assay the enzyme and then to study its properties. And to hopefully develop inhibitors which might have great drug actions. So all those things turned out to be true, but we didn't know that at the time.

Rosenberg: What year did that actually occur, those early conversations with John? And who was party to them?

Cushman: Well, as I recall, initially it was pretty much myself; my former boss in the biochemistry department; Zola Horovitz, who was head of the pharmacology department; and John. Somewhat later, Dr. Ondetti, my collaborator, became involved in this, and he became more interested in a different aspect of the snake venom peptide. But this would have been late 1967. I'm not sure of the exact month or anything.

Rosenberg: Can you tell me a little bit about what your response and that of your Squibb colleagues was to this suggestion by John Vane?

Cushman: Well, my response was very, very positive because I was working on a dead-end project. I mean we were doing a lot of hard work, but it was obviously not going anywhere, and I kind of drooled at the idea of working with peptidases. There are many more techniques available, you know, for the enzymologist to study them. And this was an enzyme that nothing was known about, so it was an absolutely open area for me to study as an enzymologist. So I was very, very excited about it. I know Zola Horovitz was also, but I'm not sure that anybody, of course, was expecting a whole lot out of it. In fact, it took us a long time before the company got extremely excited. Companies tend to get very excited about something when you've finally got that product that they know they can sell. But, you know, there are a lot of far-thinking people who thought this would be a good project to work on and thought it would be ideal for me too.

Part 2: A Detailed Look at the Discovery Process
Work on the project had been shelved more or less, when a paper by Byers and Wolfenden sparked the idea that led to the final discovery. Dr. Cushman provides a step-by-step description of the process.


Rosenberg: Dave, when you and Zola and whoever else, expressed interest in this idea, who had to give it the go-ahead?

Cushman: You know, I really don't know. I think actually probably Zola had enough power to give it the go-ahead at that time. And I would say one thing—one thing that was very exciting to me about this whole era—was that this was kind of a different time, and Squibb Institute at that time really was an institute. It was a drug company, but there was a lot of freedom, and people were given a chance to take a chance on certain things. We weren't really meddled with in much of any way on this project. I'm not sure what the powers that be thought of it or whether they thought it had great potential. I know that at the time we had drug candidates that everybody thought were really hot that turned out later not to be. But pretty much we were given a free reign on this. And that was one of the great things about it. We had a chance to do real science at an early stage and to work with outside investigators, for which John Vane was very helpful. It was a perfect environment. So I don't recall ever having any sense that anything more was necessary than Zola Horovitz's approval, and he was the head of the pharmacology department to which I had just moved.

Rosenberg: How long did you and Miguel and whatever your team was work before you had the notion that you really did have a drug candidate?

Cushman: Well, now Miguel got interested in this project around 1968 when John Vane, again, had told us that there was in this snake venom an active factor, which he thought inhibited the enzyme. So that would be 1968 when Miguel and I really started to collaborate, and that was the beginning of a wonderful working relationship. So from '68 to about 1970 really was all that was necessary to come up with a candidate. Unfortunately that candidate had some limitations. This was teprotide, which was a nonapeptide, and it was a very potent inhibitor of angiotensin converting enzyme. In fact, it worked in the clinic, and it lowered blood pressure in hypertensive patients, and I've been told maybe saved the life of at least one women who had to take it for a long time.

I had been working on the enzyme from late 1967 to late 1968, and we had an assay available, which was very important. And so Miguel and I started to work together. He was isolating peptides, and I has assaying their activity against the enzyme. So from that time, 1968 to about 1970, it was two years and we had developed teprotide, which really proved to most key investigators the utility of inhibitors of the renin-angiotensin system in lowering blood pressure. But it didn't develop a drug yet, because it wasn't orally active and there were other problems in developing large peptides for potential drug use. And the idea of making it orally active was probably a pipedream.

Rosenberg: So what did you guys do then?

Cushman: Well, this was the point where actually our immediate supervisors and all that, pretty much suggested that we should work on something else—which we started to do. But we still maintained contact and were still working on different aspects of this project. Fortunately, it didn't take us long. Well, I would say it was around 1972 when we were discouraged from this project because—well, there were positive clinical results with teprotide—but the lack of interest in pursuing this particular drug into the clinic. So when in March of '73, fortunately you had one of those little things that wasn't exactly "eureka," but I was reading a bunch of cards that we had sent out about possible new drugs and one of them referred to a paper that had been written a little while ago by Byers and Wolfenden on an extremely potent new type of inhibitor of carboxypeptidase A.

That rang a bell right away because we had been thinking for a long time that angiotensin converting enzyme was probably very similar to carboxypeptidase A, maybe related from an evolutionary point of view. So when Byers and Wolfenden described this inhibitor that they had developed, a very simple inhibitor of carboxypeptidase A, we got very excited and started to talk about it. What they had was a compound that was structurally very similar to the terminal amino acid of the substrate for carboxypeptidase A or product, if you will, the amino acid product. (This inhibitor also contained a succinyl carboxyl group.) They weren't quite sure what to make of that. They called it a biproduct inhibitor, spelled B-I product, whereas they thought it represented in one molecule, interactions with the enzyme that might be characteristic of both of these products. The terminal carboxyl group of one product and the aromatic amino acid being the other product.

So we discussed this and Miguel and I, I think, probably immediately came to the conclusion that that extra carboxyl group that they had, which they said corresponded to the carboxyl terminal group of the other product, probably was binding to the zinc ion at the active site of carboxypeptidase A, which was known to be involved in catalysis and that was a key assumption on our part. We also assumed that our enzymes being similar, but different, having a dipeptide product, maybe we could make a simple molecule that was an analog of a dipeptide, but also had a succinyl group on it to interact with the zinc ion of the enzyme. And that led us to a very simple compound, succinyl proline, which was probably pretty disappointing as an enzyme inhibitor, but of course it didn't take us long to test this. But it turned out to have some specificity for angiotensin converting enzyme and gave us encouragement.

To get ahead a little bit here, at this point it was just a matter on paper of one, two, three and we had captopril. It didn't quite happen that fast, but what happened was from our studies with snake venom peptides we knew that probably the best terminal sequence for inhibitors of angiotensin converting enzyme was phenylalanylalanyl proline, so the dipeptide product that we should probably mimic would be alanyl proline. The succinyl proline we made really mimicked glycyl proline, so we made a compound, 2-methyl succinyl proline, that mimics the structure of alanyl proline, probably the best dipeptide for interacting with angiotensin converting enzyme, and still maintaining the zinc binding carboxyl group. And it was even better, and very shortly thereafter, we started looking at the various interactions we'd proposed and found that the only one that wasn't optimal was the so-called interaction with the zinc by this carboxyl group.

And it wasn't long before we tried other groups, and sulfhydryl group was tried, and it was suddenly a thousand times more active than its preceding compound. I remember when my assistant Mr. Cheung tested that compound, we looked at the result, and we didn't believe it at first. We figured something was wrong with the dilutions of the inhibitor, but after repeating it a few times, we knew we had something that was going to be really exciting. It was so potent that it was probably among the most potent enzyme inhibitors known at that time. So we knew we were onto something pretty exciting here.

Part 3: In Praise of Zola Horovitz
Dr. Cushman relates how the head of the pharmacology department may have protected him and Dr. Ondetti from pressures to end the work on what would be the discovery of captopril. Once the discovery was made, it moved quickly into clinical studies.

Rosenberg: Dave, did you really know right away that this was a real breakthrough? When you realized it wasn't an error in dilution?

Cushman: Yeah, I did. Some things you just know. I've had maybe one or two things in my career previous to that where I discovered something important from nature, and yeah, you just feel it right away. In the back of my mind, I knew this compound would have to be orally active also, because even one of the much weaker precursors was already orally active. And this was so potent and, at least from my point of view, the more specific interactions you had with your receptor, in this case the enzyme, the more likely it was to be extremely specific. And that should carry over in the clinic to a great specificity also, which as it turns out it did. So it just seemed to have everything going for it.

Rosenberg: So where are we now in time, Dave?

Cushman: I'm a little weak on that to be honest with you. I think it was 1977.

Rosenberg: Let me take you back just a little bit because I was curious about your statement that somewhere around 1972, you were encouraged to drop this and go do something else. And you know I'd heard that story too. And I'm curious, how insistent were people that you go in a different direction and how resistant did you and Miguel have to be?

Cushman: I don't know about Miguel. Fortunately, I was pretty naive at the time so I didn't realize... Apparently they were fairly insistent at certain levels. Fortunately, we had, at least in my case, I had my hero Zola Horovitz, who didn't really tell me probably all the things that were being pushed on him. But I didn't really feel too much pressure myself. I was prepared to do some other kinds of work, but it was made very clear that we would continue to do some work on angiotensin converting enzyme also. There were some villains in the case. In fact, Arnold Welch once wrote an article about it some time ago. He didn't actually mention names, but there were some people who were very negative. It was kind of the old game of "we don't know what to do with something like this." There is no way they are ever going to develop a useful drug from this approach. But there were plenty of heroes, too, and there were plenty of people who supported it.

Rosenberg: Did some of the doubters come from the science side as well as the business side?

Cushman: Not too much. I think there were doubters in the world as a whole. But that's what you'd expect. It's probably even easier to publish things that are negative than positive sometimes. There were people who at various stages just didn't believe that the renin-angiotensin system played any role, and I think they probably at some early point weren't quite sure that even these inhibitors that we were developing were going to prove much. I think it took people awhile to realize that we were onto something real here. Fortunately, we did our job and published plenty on it, so that I think we gave the world a pretty good view of what we had actually done.

Rosenberg: What made you guys willing to go against the advice or maybe even more than advice, the orders to turn your attention somewhere else?

Cushman: I don't know, we probably didn't even know about it—I mean in terms of what was happening at a very high level. See, we weren't that important. That was the good news. I was a fairly new biochemist, and Miguel had been working on peptides for a long time, but neither one of us was an administrator. Well, Miguel was a group leader, but we weren't middle managers or anything. We weren't somebody whose time was being looked at that closely. And we had people above us who were probably protecting us from some of the flack that might have been coming down. And we were still working on this part-time. We were doing what was expected of us, which was to start new projects. I was working on prostaglandins and Miguel was working on antibiotics, but at the same time we were still communicating with each other. And we had these assays available, so we still were trying a few things. One of those few things turned out to work beautifully, and wonderfully if you will, and so after that point pretty soon nobody was complaining too much.

Rosenberg: When you had this dramatic result with captopril, how long did it take before you then found the drug in the clinic?

Cushman: I'm sure it was studied within months. There were several people out there who were still very, very interested in this whole thing. John Laragh was one of them. I don't think John Laragh was actually the first person to test it, but there were some other investigators, one of whose names is evading me right now, who tested it in the clinic and quite soon they started turning out papers on the utility of converting enzyme inhibitors. In Laragh's case, he was now pushing converting enzyme inhibitors above beta blockers, which he had been pushing as inhibitors of the renin-angiotensin system. So it was very, very quick then. From '77, when this compound was synthesized, it only took four years to have it actually approved. Unfortunately, it was approved for a somewhat more limited indication than it should have been. So it was really rapid at that point. We'd done our homework ourselves so that by the time we were in the process of synthesizing captopril, we had a lot of background information. So it went pretty smoothly.

Part 4: On Snags In the Clinical Trials and On Dr. Cushman's Early Education
Side effects from large doses beset some of the clinical trials of captopril at first. Dr. Cushman also recounts his upbringing and education in Indianapolis. He says a high school biology teacher really set him on the path to becoming a scientist.

Rosenberg: Was it completely smooth sailing from the time of synthesis? Or were there some other moments when things seemed very rocky?

Cushman: Well, there were a few, but it's the usual thing. To be honest, what it came down to is that our medical department, among others, had never had a really big drug before, number one. Not for years anyway. So it was a little bit more difficult for them than it might have been otherwise to hit something with this potential. So they had a few ups and downs in terms of developing it, and there were always a few people—it's very easy to get scared in a thing like this. I had never been involved in the development of a drug in the clinic myself. So when it turned out that we gave very high doses of the drug, which was quite possible because it's not toxic, to patients in the Cleveland Clinic, a lot of them got rashes. So all of a sudden the drug had a reputation for causing rashes, which wasn't so bad.

Then later it started having a reputation for causing changes in white cell counts, which was bad. Most of these were very, very sick patients, and it took quite a while there to rid people of this interpretation that somehow this drug had side effects (that) were unrelated to its action as an angiotensin converting inhibitor. The Merck people jumped all over the idea that it was a sulfhydryl compound, because some sulfhydryl compounds with other groups on them are (metal) chelating agents and can have some fairly profound effects. But captopril was not a chelating agent and doesn't really have the kind of effects they were trying to make people worry about. I guess, because they were developing ones that didn't have sulfhydryl compounds.

So there was a lot of static, and just like anything else, if you read the news every day instead of reading it once a month, you get weird interpretations about what's going on. The same way with drug development. You can get easily scared. But fortunately they got through all that, and it turned out to be a very, very useful drug in the clinic and even more useful for indications that we hadn't thought of at the time. I think probably heart failure was a really big surprise and possibly one of the most exciting uses of the drug.

Rosenberg: Dave, are you surprised at the, sort of the pathway of utility that captopril has followed going from hypertension to heart failure to post myocardial infarct patients to diabetics? Did you have any inkling of the remarkable breadths of utility clinically that it was going to show?

Cushman: No. I was surprised obviously like everybody else. The only thing—I'm the optimist in the crew, by the way—so I mean I was always, "Oh well, this will work out." The only thing I believed and still do, from the very start I thought we were working with an agent, angiotensin II, which probably plays key roles in medicine. So I think we were looking for some surprises along the way, but I don't think any of us even came close to believing it would be as exciting as it was. And for the naysayers in the company, I think the fact that it was making a billion dollars a year at its height was a pretty good path for them.

Rosenberg: I'm sure the doubters decreased in number rapidly when the commercial success became apparent.

Cushman: Yeah. I think there is a principal here, too, that I always believed in, although I was fairly young and naive about pharmacology, but basically that there is nothing better than a really specific, what the British would call a spanner in the works. Being able to mess up a system specifically is one of the best ways to find out what it really does. I think probably captopril has been a good example of that, and there have been some other drugs that have come along in recent years with that kind of specificity that are showing the same thing now.

Rosenberg: Dave, let me turn away a bit from the wonderful story of captopril to get a little bit more information about you and how you found yourselves in a position to do this work. Tell me a little bit about yourself. Where were you born and how did you grow up and what were the things that led you to become a scientist?

Cushman: Okay, I really want to do that. Yeah, I grew up in Indianapolis, Indiana, which is far away from everything cultural. At least at the time it was particularly far from everything cultural. And I was a bright kid, I think, but a very poor student. So I got along on doing very little work until I was in high school. In my sophomore year, I think I got an F in world history. So I started to realize that maybe I wasn't going to be able to get along without doing any work. And I got very excited by a course taught by my high-school biology teacher. His name was Mr. Philip Fordyce. And he's the guy that really set me straight in the academic pursuits, because I so wanted to impress him and so enjoyed his course that it sort of made me get more interested in all my courses and become more of a student.

By the time I 'd finished high school, I had a good enough academic record so I got a scholarship to Wabash College in Crawfordsville, Indiana, which is a very fine liberal arts institution of the type we don't see that much. It's all male, which was probably my social undoing. The other influence in my life was that I was poor. I wish I could get that across to my kids. Being poor is a great stimulus for wanting to achieve something. So anyway, I got to Wabash and did very well, you know, graduated magna cum laude and got a National Science Foundation Fellowship to the University of Illinois to study biochemistry, and I was pretty much on my way at that point.

At Illinois, I spent about five years catching up on some of my science I should have learned earlier in my career and studying microbial enzymes. My boss, Dr. Gunsalus at Illinois, sent me to interview at Dupont, I think probably to scare me away from industry. But I was really impressed by them, although they weren't very impressed by me because I hadn't really done enough at the time when I interviewed with them. So that got me interested in looking around at industry. I think I still felt that I might end up in academia, but I really wasn't too interested in going on and getting a post doc, particularly since I would have been working with one of my boss's friends, probably. I thought if I went to work in industry, I could be independent and maybe make a name for myself. If I wanted to move back into academia later I could, which I never did, of course.

So I went to work after five years of graduate school. I accepted a job at the Squibb Institute for Medical Research, which is now at Bristol-Myers, Pharmaceutical Research Institute, Bristol-Myers Squibb, after a takeover. As I told you before, I was working on enzymes from Australian plants that introduced fluorine atoms into molecules to form fluoroacetic acid, and that just didn't have enough of the right factors. I learned a lot of good techniques, but it just wasn't going anywhere, when John Vane came along. Or actually I was switched—our department of biochemistry was done away with. I switched into Zola Horovitz's pharmacology department. (Horowitz) was the only biochemist in the department, and John Vane came along and suggested this project. So that's my career in a nutshell.

Part 5: Tribute to John Vane and a Nod to Shakespeare
Dr. Cushman talks about the influence of John Vane and others on his career, then describes some of his interests outside of science. They include Shakespeare and comic books.

Cushman: I had to mention Mr. Fordyce because he was such an influence in my life. You know, you don't get a chance that often to tell an old teacher what they meant to you.

Rosenberg: Have you communicated with him since you have become rather a celebrity?

Cushman: I knew he was in Florida. I looked up his phone number on the Internet and I called up and said—you know I got an answering machine—I told him if he was indeed Mr. Fordyce, I would enjoy talking to him sometime or he could write me back. I really didn't get any answer at that time. I think I had the right number. He's an older man now. It turns out his daughter went to school with me, too, so when our 25th or 30th high school anniversary thing came out, they put out a booklet. So I put some statement in there about how much he had meant to me, and she got a hold of that and told him about it. I'll definitely send him some information on the Lasker Award. I'll probably send it to his daughter and have her... he may not be well. I don't know.

Rosenberg: Dave, did you come from a science family?

Cushman: No, no, I came from a family that had no tradition of even going to college, so to me initially going to college wasn't even on my horizon. I had loving parents, who didn't have too many expectations, I guess. They were from the Depression generation. They had raised a lot of kids, and there weren't a lot of books around. My mother was more interested in reading and education than my father, I think. But you know, it just wasn't... I kind of had to discover that aspect of life myself.

Rosenberg: You said your parents had raised a number of children. Were you sort of late in the list of kids in your family?

Cushman: I was second. I was the first one to go to college. My sister went to...we had a choice: We lived in a part of Indianapolis where you could go to one of two (high schools). My sister picked Arsenal Technical School, which from the name you can guess probably didn't turn out a lot of college-bound students. I picked Broad Ripple High School, which at the time was one of the best schools in the town in terms of turning out college-bound people. That was a good choice. I may have made it for the wrong reasons. I probably knew people who were going there and felt it was a little closer, but that's where I met this biology professor that stimulated my career. It's one of those things, you know, my kids have the curse of being well-off. So, I can't pass that on to them.

Rosenberg: I think I have some idea of what you mean there. Dave, I'm curious about your very clear admiration and affection for Mr. Fordyce. What other people in your life would you classify as your heros or role models or people who really influenced what you became?

Cushman: Well, you always run the risk of leaving people out, but I think there were two who just were so profound that they have to top the list. Anybody I leave out, I apologize for. The other one was John Vane. It wasn't just because John Vane was a good consultant. I always considered John Vane my friend. I even used to kid him I wasn't going to call him Sir John. But, yeah, I've always considered John a friend. He was either a great friend or a perfect consultant in that he was kind of my mentor. And he was not only helpful in suggesting projects and things like that, but discussing ideas with us, over and over again. And actually John introduced me to a lot of people in the field. So I got to the point where I knew more academic people in the field of hypertension than in other drug companies, which was very unusual for a person working at a drug company. Most of these people know all the other drug company workers. I didn't know all the academic people working in the medical fields, but he did a lot of good things for me. And he doesn't always feel completely appreciated, although I think winning the Nobel Prize is a pretty good sign of appreciation. But he definitely was essential for my life, along with my high school biology professor.

Rosenberg: Well, those are two singular folks with very different contributions.

Cushman: Yeah, I should also add Zola Horovitz to that list, too. I was very lucky in having a boss...I mean, I never considered Zola a boss. We were colleagues. The best bosses are never bosses. Zola was a terrific influence on me. I think he protected me from a lot of junk I didn't need to know about and was very, very, very important for the development of this program.

Rosenberg: Dave, let me again take off in a slightly different direction. You and I both know that when people read about scientists, they're always curious about what kind of folks these are. Are they absolutely singular in their interests? Are they workaholics? Do they care about anything else? How would you characterize yourself as a human being? What other things do you enjoy? What things give you pleasure? How do you spend your time—or how did you spend your time when you were an active scientist, other than when you were working?

Cushman: Well, I'm probably not typical actually of a lot of scientists in that, I guess part of it is, I had what I thought was a very great undergraduate education, a true liberal arts education, which maybe shouldn't have lasted as long as it did, four years, but nonetheless it stimulated in me an interest in learning of all kinds. So I have a number of really strange and conflicting interests. I enjoy playing golf very much. I'm much, much more interested in history than I ever was when I was in school. And the history, that can be added to by traveling and visiting places, you know. I'm still very active at that.

I've gotten, if anything, more interested in languages as I've gotten older. Even in retirement, I've been taking Italian and German courses. I suspect I'll continue to take some French and Spanish courses, as well, and maybe eventually put them all together and come up with some ability to speak in some of those languages. I came up late in life with an interest in the opera, so I spend a lot of time going to the operas. I think my initial interest in Italian came from the fact that it seemed like a very easy language for me in these librettos. I still read a lot and try to keep up with some things intellectual. I still read poetry, now and then, catch up on some of Shakespeare's plays. And of course the other side of me, there is a side, I collect old comic books. So I spend an awful lot of time reading comic books. It may not go along with Shakespeare exactly, but it's recapturing my youth.

Part 6: Retirement and Why He Took It Early
A number of factors came together to prompt Dr. Cushman to retire from Bristol-Myers Squibb at age 54.

Rosenberg: Are you married, Dave? Do you have a family?

Cushman: Yeah, my wife's name is Linda. I have a son, Michael, who got married and gave us a grandson a year ago. And my daughter, Laura, is still living with us. She's doing local archeological work and hasn't quite made enough money yet to get her own house or hasn't found a rich man yet.

Rosenberg: How old were you, Dave, when you left Bristol?

Cushman: I was fifty-four. I took early retirement. This is another thing that's atypical about me.

Rosenberg: Can you give me an idea why you did that?

Cushman: In essence, I'll be honest with you, I think part of it—I may have high expectations—I think part of it is that as you get older, you don't always get as much, what's the word...it's like there's a conspiracy to keep you from being creative. I think it happens a lot of times in academic places when people become administrators, rather than scientists. There was not only (that) everything was trying to conspire to get me to do other things other than basic research, which is what I wanted to do, but also the old guy versus the whippersnappers. You sometimes feel that people don't have as much respect for you as you get older, and some people that have accepted the administrative jobs make it a little more difficult for you to do what you really want to do, even what's good for the company, I think.

Just all in all, I thought about retiring early several years before I did, fortunately because I was able to financially be able to do it. It's not a religion with me to work for a living, so I thought I have a lot of interests. And I had a medical problem, too, and I wasn't sure how long I might be fit. I think probably now, as things stand, I'll be fit for a very long time. But you know to be able to travel and do things like that, you have to be able to handle it physically and everything else. There were just a lot of things that kind of led me in that direction.

Rosenberg: Well, I'd have to say you're a very fortunate man. You not only have made a remarkable scientific discovery, but you sound as if other things in life matter a great deal to you, and I guess that is not always the case.

Cushman: No, a lot of people couldn't stand to be retired. It's as simple as that. You know, science is a difficult mistress, isn't it? If you do it right, you spend so much time trying to keep up with the literature and trying to maintain your position in science so that you're still...in academia it's probably even worse than in a company...You're trying to make sure that you still have the resume that indicates that you're worth hiring if you do want to move somewhere else. You really just have to spend so much time keeping up with what's going on in the world...It probably interfered with my family life pretty early in my career. To be honest with you, it was kind of a relief to get rid of that. I feel a little guilty now that I don't know what's going on, but it is so much of a relief not to have to go read reprints and the like all the time.

Rosenberg: Well, Dave, I think we've covered the things that we needed to cover. I want to thank you very much for taking the time to talk to me, and, again, I just want to tell you how pleased I am not only on my own behalf, but on the behalf of lots and lots of other people. It's a pleasure to hear your story a bit. I'm sorry that you and I didn't get to know each other better when I came to Bristol-Myers Squibb.

Cushman: I was going to say that to you. There wasn't much of an interval there when we were working at the same time.

Rosenberg: No, but this gives me a chance to go back a little bit into the lore of that company and maybe some of the very best of it, and I very much appreciate the opportunity to talk with you about it.

Cushman: Well, I certainly appreciated talking to you. I never had a chance before. I enjoyed it a lot.

Rosenberg: Thanks very much.

Key Publications of David Cushman

Cushman, D.W., Plusec, J., Williams, H.J., Weaver, E.R., Sabo, E.F., Kocy, O., Cheung, H.S., and Ondetti, M.A. (1973) Inhibition of angiotensin-converting enzyme by analogs of peptides from Bothrops jacaraca venom. Experientia 29: 1032–1035.

Ondetti, M.A., Rubin, B., and Cushman, D.W. (1977) Design of specific inhibitors of angiotensin-converting enzyme: new class of orally active antihypertensive agents. Science 196: 441–444.

Cushman, D.W., Cheung, H.S., Sabo, E.F., Ondetti, M.A. (1978) Design of potent competitive inhibitors of angiotensin-converting enzyme, carboxyalkanoyl and mercaptoalkanoyl amino acids. Biochemistry 16: 5484–5491.

Ondetti, M.A., Condon, M.E., Reid, J., Sabo, E.F. Cheung, H.S., Cushman, D.W. (1979) Design of specific inhibitors of carboxypeptidases. A and B. Biochemistry 18:1427–1430.

Cheung, H.S., Wang, F.L., Ondetti, M.A., Sabo, E.F., and Cushman, D.W. (1980) Binding of peptide substrates and inhibitors of angiotensins-converting enzyme: importance of the carboxyl-terminal dipeptide sequence. J. Biol. Chem. 225: 410–417.

Cushman, D.W. and Ondetti, M.A. History of the design of Captopril and related inhibitors of angiotensin converting enzyme. (1992) Hypertension 17: 589–592.

Miguel A. Ondetti

Nature Medicine Essay

Miguel Ondetti interviewed by Leon Rosenberg 

Leon Rosenberg, Professor, Department of Molecular Biology and the Woodrow Wilson School of Public and International Affairs, Princeton University, interviews Miguel Ondetti, who shares the 1999 Albert Lasker Clinical Medical Research Award with David Cushman. Dr. Ondetti, now retired, was senior vice-president for cardiovascular metabolic diseases at the Bristol-Myers Squibb Pharmaceutical Research Institute in Princeton, NJ. Dr. Rosenberg is also president and chief executive officer of the Funding First initiative of the Mary Woodard Charitable Trust, August 1999.

Part 1: Education In Argentina and Early Influences
Dr. Ondetti talks about his education at the University of Argentina, his mentor at the Squibb Institute in Buenos Aires, and his decision to come to the United States.

Rosenberg: Miguel, I'm delighted to have a chance to talk with you, first to congratulate you one more time on your being the recipient of this year's Lasker Award for Clinical Research. As somebody who had reason to be associated with you at Bristol-Meyer Squibb, it is a particular pleasure to have a chance to interview you and to find out a bit about how this work came about. So let me ask you first...tell me where you were born...a bit about your early years. I know you were not born in the United States, but I'm curious as to your beginnings.

Ondetti: Yes, I was born in Buenos Aires, Argentina, and I received my education in Buenos Aires at the School of Science of the University of Buenos Aires. I came to Squibb because I was the recipient of a scholarship for training in scientific research to work with Dr. Deulofeu, who was then the head of chemistry at the Squibb Institute for Medical Research.

Rosenberg: Now, Miguel, this was not the Squibb Institute here? This was the Squibb Institute in Buenos Aires?

Ondetti: Yes, but it was really a branch of the Squibb Institute here that had been built in the early '50s by the Squibb Company in Argentina.

Rosenberg: Was Dr. Deulofeu a senior person in the Squibb Institute in Argentina?

Ondetti: Yes. When I came to the institute, the head of the institute was Dr. Sordelli, who was a very well-known microbiologist. He was world-renowned in microbiology. He was the head of the institute and Dr. Deulofeu was the head of the chemistry part of it. I was working on a project proposed by Dr. Deulofeu on the chemistry of carbohydrates that was eventually part of my doctoral thesis.

Rosenberg: Would you say that Dr. Deulofeu was an important mentor for you in your early scientific years.

Ondetti: Oh, very much so. He had been my professor of organic chemistry at the University and for me was a representation of what research was or was meant to be in chemistry. He was the dean of chemistry in Argentina and recognized by a very large, long series of collaborators. So for me to work with him was not only a great learning experience, but really what encouraged me to continue in research.

Rosenberg: Miguel, how old were you when you first met Dr. Deulofeu and how long were you associated with him actively in research?

Ondetti: As I said, I met him first as a student in the University in 1953. But I started collaborating with him in 1956 until I came here in 1960.

Rosenberg: So you worked closely with him for four years.

Ondetti: Exactly.

Rosenberg: And maybe you'd like to tell us about the circumstances that led you to come to the US.

Ondetti: After I finished my doctoral thesis work with the scholarship from Squibb, I was offered a position as a full member of the scientific staff. So I joined them in 1957, and I was working on the isolation of natural product, alkaloid, from South American plants for three years. And in March of 1960, Dr. Deulofeu's secretary called me to his office and said that Dr. Langlyke, who was then the head of the Squibb Institute here in the US, and he normally, routinely every year paid a visit to the Squibb Institute branch in Buenos Aires, that he wanted to talk to me. And when I went to the office, Dr. Langlyke right away off the bat asked me whether I wanted to work in the United States.

Then I asked him for how long and he said for as long as I wanted to work. That he was offering me actually a position, a permanent position of the Squibb Institute and that I had two days to think about it and give him an answer because he was leaving for the States in two days. So I discussed it very thoroughly with my wife, who was ready to open her office as a dentist, and we decided that we were going to take the chance, because we could always come back—and that was 39 years ago. We never did. So we're still here. So that's how I came to work at the Squibb Institute in the United States.

Rosenberg: Have you ever regretted, Miguel, that decision?

Ondetti: Well, no. Regretted, no. I have thought that there would have been a number of other things that I could have done if I had gone back and joined the handful of people who had been my classmates, that they are now in good positions, in very high positions at the University. But I didn't, by the same token that I never regretted that I went to Squibb, an industrial lab, and I never left. I felt that I had found my niche in which I could work in collaboration, not only with chemists, but we also with biologists. That was very important to me.

Rosenberg: Do you think you would have discovered captopril if you had not come to the United States?

Ondetti: No. I guess the answer is almost certain.

Rosenberg: Why?

Ondetti: Well, because there were a number of circumstances that had to sort of come together. And even though I was always interested in chemistry that was connected with biology, it is more difficult to have that connection when you are working in a completely academic chemistry department. It's much more feasible when you work in a pharmaceutical company. And I think that's one of the key important points of my career.

Part 2: Initial Work on Peptide Synthesis at Squibb in the United States Proves Useful as Interest Turns Toward the Renin-Angiotensin System
Earlier tedious work in peptide synthesis proves an advantage when Dr. Ondetti joins John Vane and David Cushman in a search for converting enzyme inhibitor. That work produces teprotide, a compound that attracts interest from clinical investigators. The company, however, decides not to put any more effort into the angiotensin converting enzyme.

Rosenberg: So now let's pick up again on your adventure after you came to the US. How did your work begin here and how did it come toward the renin-angiotensin system?

Ondetti: Well, when I came here, the head of chemistry at Squibb was Dr. Gus (Joseph) Fried who had made a very important name in the chemistry of steroids. And honestly I was hoping that I was going to be allowed to work on the chemistry of steroids, but he told me that they had decided that I was going to join the team of peptide synthesis that was headed by Dr. Bodanszky, who had been working with DuVigneau, and he was hired to really initiate the project on peptide synthesis. I was a little bit disappointed at the beginning because peptide synthesis for a chemist sounds, and is considered by many, kind of repetitious.

But I was very soon taken over by the tremendous value of peptides in biology, by the large variety of biological functions that are controlled by peptide. And I began working with him interestingly enough, just a coincidence...he asked me to synthesize bradykinin because the structure had been discovered, proposed first wrongly. And he had made the wrong structure. So he asked me to re-synthesize. We had what we believed to be, correctly so, the right structure. And that was my first peptide. And it had a tremendous impact on me.

When I took 3 milligrams, or something like that, 3 or 5 milligrams, that I had managed to purify and asked Dr. Rubin, who was going to be my collaborator for many, many years, if it was enough to test. He said if it is bradykinin, it should be enough. Then he called me afterward and told me that to get the compound within the range of the contractile activity of the muscle, it had to be diluted with a liter of water, taken and diluted again with a liter of water and taken again and diluted some more.... I think he said the compound is active at the level of less than a nanogram. At that time I wasn't very sure what a nanogram was, but I was impressed by how peptides could be kind of boring for a chemist but very important for tissues.

So I worked on peptide synthesis for the best part of the '60s. Dr. Bodanszky had left to join Case Western Reserve University, and I was the leader of the group. We were working on gastrointestinal hormones and synthesized secretin and then cholecystokinin. And we managed to convince the management to put on the market one of them, cholecystokinin, as a diagnostic agent. But the interest in gastrointestinal hormones was sort of tapering off, and the head of the institute—that was Arnold Welch, who came from the Department of Pharmacology at Yale—decided that the emphasis should be on cardiovascular research. It was at that time that, through the interaction between the new consultant Dr. John Vane and Dave Cushman, that they had decided to initiate a search for converting enzyme inhibitors. And I was sort of enlisted to the do the chemistry of that area, and this is how I got involved in the renin-angiotensin system.

Rosenberg: What was the first thing that you did once you were encouraged to join that effort?

Ondetti: See for me it was like a return to a natural product chemistry because we had to purchase the venom of a Brazilian snake, a pit viper that is called the Bothrops jararaca. A Brazilian pharmacologist in Dr. Vane's lab had shown that the crude extract from this venom was able to block the conversion of angiotensin I to angiotensin II. And he had shown before that this crude extract of the venom was able to also potentiate the effect of bradykinin. That 's the reason why they originally called it BPF (bradykinin potentiating factor). Now at that time it was not known that those activities were the consequence of the action of the same enzyme. So I was asked to purchase venom from the Institute Butantan in Sao Paulo and fractionate it and isolate the compounds that were responsible for the activity. And that was the task of my chemistry group.

Rosenberg: Do you think that the potency of the venom was directly related to this action on bradykinin and on the converting enzyme?

Ondetti: I really don't know and I don't know if anybody knows that for sure now. But the venom kills by producing a very drastic drop in blood pressure and all the consequences that lead to shock...and so they may play a role. I don't know if there are also other high molecular weight compounds that have an effect but they probably do play a role.

Rosenberg: So how did the work evolve, Miguel, once you had isolated these substances from the venom? They turned out to be peptides, is that right?

Ondetti: I guess even before we started, we knew that they were going to be peptides. We didn't know that there were a large number of them. So we had to isolate several components and separate them and determine the structure and then synthesize them. And then that was one of the advantages of our previous experience with peptides because if we had any doubts on the structure, we made them and thus proved if the structure was correct or not. They were in length between 9 and 12 amino acids. So when we selected the one that we thought was the most active and that was a nonapeptide, we synthesized a large amount, sufficient for initiating all the toxicology to obtain the IND.

That compound was introduced in clinical testing in I think it was '71 or '72 with the name of teprotide. I guess because it has four residues of proline. And the studies were very interesting, even though it was an injectable drug and could only be used either subcutaneously or IV. But we had a lot of interest on the part of the clinical research community because it was a new tool to investigate the function of the renin-angiotensin system. So there was a lot of interest and a number of very important clinical investigators were conscripted to do clinical research. On the other hand, we in the lab were involved in trying to simplify the structure, because we knew that with that large size it was impossible to get oral absorption, and also in obtaining compounds that would not be degraded by digestive enzymes. We did a number of synthetic modifications, but we were not successful.

Rosenberg: And so what happened to teprotide?

Ondetti: It was maintained as a sort of a research tool, and the company was willing to provide the compound to clinical investigators but officially it was declared not a development candidate. As a matter of fact, the company decided not to put any more effort into the angiotensin converting enzyme, and some of the clinical studies which were done, were done by investigators who were interested enough to have their own financing.

Rosenberg: Who were some of those clinical investigators? Do you know?

Ondetti: Yes. John Laragh was one of them and his group that at that time—I'm not so sure where they were—still associated with him. It was Harry Gavras, who then moved to Boston. And then there was a group in France that was headed by Menard and Corvol that did a lot of very interesting work. And then the group at the Cleveland Clinic also did a significant amount of work.

Rosenberg: Was that Irving Page?

Ondetti: No, not Page himself. Irving kept in touch with the development, but he wasn't doing the clinical studies then. I don't remember exactly the name.

Part 3: Paper by Wolfenden Jump Starts Dormant Research on Angiotensin Converting Enzyme
When Dr. Cushman see a paper on the inhibitors of carboxypeptidase, he and Dr. Ondetti see new possibilities for their ACE research. Captopril is synthesized in October 1975.


Rosenberg: So in 1971 or 1972, the company decided to de-emphasize, in fact to discontinue, work on the converting enzyme. How did you feel about that and what did you then pursue?

Ondetti: Well, it was a disappointment, not necessarily for the work of converting enzyme, because we knew the direction in which we were going wasn't productive. I mean we had done it. But the company made a more radical change. They decided to actually terminate all the work on peptides. They felt, like many other companies had felt on and off, that peptides are very unlikely to become drugs in the way that people were interested—with the oral absorption. So they felt that they had to put more importance on other projects, and they asked me to be the head of the antibiotic research in chemistry.

It was not a happy occasion, and I did consider whether I should sever my association with Squibb or to continue. I had sort of developed a name in peptide synthesis through my work. But I found the work on antibiotics challenging enough, and I had a certain degree of freedom to do some projects on my own with my assistant Emily, so I took on antibiotic research with great zest, waiting for the time that things would change. And they did change.

Rosenberg: Now how did that change come about, Miguel? When and how?

Ondetti: I think it was in March 1974 that I received a brief note from Zola Horovitz's desk in which he attached a comment from Dave Cushman saying how interesting was this paper by Wolfenden on the inhibitors of carboxypeptidase. And Zola wanted to know whether we could get the compound to test whether it would be an inhibitor of a converting enzyme.

Rosenberg: Now why was there a thought that something that was an inhibitor of carboxypeptidase might be an inhibitor of ACE (angiotensin converting emzyme)? After all, inhibitors usually are very specific, and enzymes have great specificity.

Ondetti: I think the idea came about because during the time that I was doing the isolation of the peptides from the venom, we were also working in collaboration with David to know more about the converting enzyme. Dave had isolated and purified it from the lungs, and he had looked at the properties of the enzyme. His feeling was that it was a zinc metalloprotease like carboxypeptidase. But converting enzyme somehow had evolved to be able to cut two amino acids from the carboxyl end of the chain. While carboxypeptidase, as you know, cleaves only one amino acid, and carboxypeptidase has a great specificity for aromatic amino acids, while converting enzyme has not very strong specificity.

But we had found that, interestingly enough it did prefer compounds that had C terminal amino acid proline. So when Dave saw that paper, it wasn't that he believed that the compound was going to be an inhibitor of angiotensin converting enzyme, but he thought that, well, this enzyme was closely related to a converting enzyme and since enzymes do belong in families and have similar mechanisms, maybe one could use the same rationale.

So I never really made any attempt to get the compound that Wolfenden had—it was benzyl succinic acid. As a matter of fact, I don't think we ever tested it. We knew that it couldn't be. But we got together, and we discussed what did it mean, this observation, for our studies on angiotensin converting enzyme. And then we decided to get going on it. So March 1974 was really the beginning of our going back to the project.

Rosenberg: How easy was it for you to get approval to return to this area? Did you have to seek permission or did you guys just make up your mind you were going to do it?

Ondetti: No, we didn't officially seek permission or approval of the project as such—for a number of reasons. One of them was that we had a certain degree of flexibility in terms of work that we could do that we didn't have to actually report every single compound that we made. And second, I guess, in the back of our mind we knew that Zola was going to support it. And Zola was the head of all the biology. He was an associate director for the Institute in charge of all the biology and there was Pat Diassi, who was the head of the chemistry as an associate director. But as I told you, I was told to assume that my assistant Emily could be working on any project that I chose.

We told them it was an exciting idea, and it was something that we discussed the generalities of the hypothetical active side of the enzyme and said, "Listen, make the simplest compound to prove if we are in the right direction." And Emily made that first compound before she left on vacation in April, and that was succinyl proline. Dave Cushman found it was active, but very poorly active. But what was more important is that Bernie Rubin had been involved with us in the ACE program and had developed a combined assay using guinea pig ileum using angiotensin I and bradykinin. He said this compound behaves like a specific inhibitor, even though it was like a thousand times less active teprotide. So we said, (laughter) "We're back."

Rosenberg: Where did you go from there?

Ondetti: Well, then when Emily came back, we just started modifying this basic structure. But we had the idea from the very beginning that the important portion of the molecule was the carboxyl that was acting as a ligand for the zinc in the enzyme. So we started to try different groups that might also act as ligands, and that's how we ended up with the sulfhydryl group. And that's what led to the synthesis of captopril, and that was done in October 1975 for the first time.

Rosenberg: So that was really only a year and half from the time of the Wolfenden paper?

Ondetti: From the time that we decided to go back, it was a year and a half.

Rosenberg: Which was really very fast.

Ondetti: It was very fast by the standard for other areas, and I guess it was because we had an outline of the path that it was very straightforward. We didn't try to make a large number of synthetic compounds. We just were thinking about what this hypothetical side was telling us. Interestingly enough, if you look back now after many years, most of the ACE inhibitors that have been developed have maintained the structure or the underpinnings of our SAR (structure activity relationships) from the very beginning.

Rosenberg: Miguel, from the time that you tried succinyl proline, approximately how many compounds did you test before you got to captopril?

Ondetti: I think once we did a count...less than 100. It is interesting that before we dropped the angiotensin converting enzyme program, we had searched from all the files of the Squibb 2,000 compounds and tested them and practically all of them were inactive. So it was a big difference. I mean when you were on the right track and you knew what you were trying to get, that you could plan better.If you looked at the comparative activity of succinyl proline and captopril, it's like four orders of magnitude that was achieved in 100 compounds or thereabout.

Rosenberg: That's a remarkable....

Ondetti: It was a fairly direct approach (laughs).

Rosenberg: I think that's an understatement. You're being a bit modest. Four orders of magnitude in less than 100 compounds means that you guys knew very much what you were looking for.

Part 4: Two Key Experiments Demonstrate Captopril's Effectiveness; Clinical Studies Follow Post Haste
Its orally active nature and potency on spontaneously hypertensive rats indicate captopril's promise. Squibb puts full support into clinical trials.

Rosenberg: Now once you found captopril, did you think captopril was in fact a drug right from the beginning?

Ondetti: I guess we didn't quite believe it until we had seen two key experiments. First of all, it was that you could achieve inhibition of the angiotensin converting enzyme orally with a milligram and that was unheard of and very striking. And the second thing is that, you know—and I think it still is being used—at that time the key screen for antihypertensive agents were the spontaneously hypertensive rats. When we found that captopril was very potent on the SHR, we knew that we had a very potent drug.

As a matter of fact we sort of argued, sort of haphazardly, with management that we should be sure that we looked for other compounds to be sure that we had the best compound, but nobody wanted to listen. They said, "This is it. This is our candidate and now we have to make so many kilograms to do toxicology and we're going to Phase I." The first Phase I studies were done in Switzerland in December 1976 (by Hans Brunner). We made a compound for the first time in '75. To have a compound clear all the development in a year, that means it was a lot of push.

Rosenberg: So what that really does mean is that once captopril was discovered, it must have attracted a great deal of support very quickly from management all the way up to get that kind of priority. Who was the CEO of Squibb then?

Ondetti: This is a very interesting story. We didn't have a president of the Institute. The Institute had no president. Zola and Diassi as associate directors were running the institute and only I think very close to the middle of '77, I'm sorry, the middle of '76 or by the end of '76, was when Dr. Mackaness was brought in.

Rosenberg: What did George think about all this?

Ondetti: Oh, George was very excited, as you can imagine...

Rosenberg: Right away?

Ondetti: Oh, yeah. Before Dr. Mackaness came we had a sort of a quote unquote interventor. Somebody who came and sort of looked over...and it was Henry Harris from Oxford. He was called in by the management, Larry Marks, who was then the quote unquote chairman of the Institute. He was called in to pass judgment and to work at the Squibb Institute. I believe they must have offered a position to him, but Henry was not interested in leaving Oxford. And I think he was the one who proposed Dr. Mackaness because George had worked at Oxford in the time of the penicillin.

Rosenberg: Miguel, it would seem to me that the kind of push that was made would have had to have the support, not only from people in science, but it would have had to have support from the people on the business side. In retrospect, who were the critical business folks who climbed on the bandwagon?

Ondetti: I think that the critical person in management at that time was Larry Marks, who had come from the legal side of the company, but I'm not exactly sure what his position was. But I think they had a certain amount of concern, because nobody had a drug of this type. And even though the animal studies were very clear, indicating that they had an antihypertensive action, there were no precedents for it. And the only other drug that had been in the clinic as a blocker of the renin-angiotensin system was a peptide that was an angiotensin II antagonist. It was called saralisin, and it hadn't done very well because it was a peptide and second, because it had some agonistic activity.

So there was some hesitation, but I guess it also played a role, the fact that there was no other compound that was so quote unquote hot at that time at Squibb. Everybody felt that, well, there was a risk--and there was a risk because we did a number of things that were not probably correct because we were the first ones to do it. There was in everybody the idea that this was a completely new type of drug, and I believe that was one of the main roles.

Part 5: Trouble and Triumph
Serious side effects in clinical studies threaten the captopril project. General use studies finally show it to be as safe or safer than other drugs for hypertension.

Ondetti: There was a time in the history of the development of captopril when I believe, even though I didn't participate in that meeting, that the decision was pending to discontinue clinical research on captopril because we had run into a number of problems.

Rosenberg: This was while it was in the clinic?

Ondetti: That's right.

Rosenberg: What were the things that were encountered?

Ondetti: Well, as I think I mentioned, is that we didn't know that blocking the renin-angiotensin system would not necessarily affect blood pressure in all hypertensive patients, but only on those in which the tone was an important factor and where volume was not. And it took us a very long and difficult time to learn that lesson and to learn that we had to use a diuretic combination. And people, to counteract this lack of response on patients, kept increasing the dose until the doses that were used were ten times what it is now assumed to be a super effective dose. The people at the Cleveland Clinic reached more than a gram per day, and then, as you can expect, everything started happening.

Rosenberg: What were the things that happened to those patients? Do you remember some of them?

Ondetti: Well, one of the first things is that a very large number of patients at those doses developed rashes, and they had to be taken off, and that in some patients renal failure set in. But particularly, there was another lesson that we had to learn very carefully. When we got into the angiotensin system, it was believed that the only applicability of this system was for people who had renovascular hypertension. We later learned that those patients are the most delicate in the sense that they had to be treated very carefully because the renin-angiotensin system is the only one that maintains the renal function, and if you remove it, these people will go into renal failure. So you had to be giving very low doses and very carefully monitored and they didn't do it. So some of these patients were precipitated into renal failure.

Rosenberg: Was that the most dangerous moment in the clinical development—the work from Cleveland?

Ondetti: Well, then we ran into trouble in a number of other places. There was a point in which there was a very critical discussion (about) whether we should discontinue.

Rosenberg: Do you know who was involved with that discussion?

Ondetti: Well, I know that George was very strongly in favor. George Mackaness. I really don't know who the people were who were very concerned about the eventual responsibilities of the company, and they wanted to call it off. I think eventually Dick Furlaud as the final arbiter prevailed and said we would have to proceed with great caution. And as you know, the first time that finally captopril was approved, it was approved with severe restrictions.

Rosenberg: That would have been in 1981?

Ondetti: Yes, but it was very fast, comparatively speaking, because they filed the NDA in '77 or '78, but it was only approved for patients in which all other medications had failed. Then what really turned the situation right around was what we called the GUS study, the general use study, that was undertaken, I think it was by John Alexander and people at the Veteran's Administration in which it was given to a very large variety of hypertensive patients in low doses. And that proved that captopril was as safe or safer than any other drug. But there were very difficult times.

As a matter of fact, I remember one of the Merrill Lynch stock analysts had coined the name or the phrase, "the saga of captopril," because everybody was excited by the way we had come out with a compound. And to think that everything was going to end up in nothing, made people very, very unhappy. So it was a tremendous turnaround when we finally got the release. And then interestingly enough, we have very few problems with congestive heart failure because it proved from the beginning that it was very beneficial and people used very small doses. So it was a tremendous feeling of excitement and sometimes very severe depression (laughs).

Rosenberg: Miguel, it's a wonderful story. It is a saga because it has moments of great exuberance and then moments of feeling despondent. There's excitement all the way through it.

Ondetti: A lot of drama.

Rosenberg: So Miguel, talking about some of the drama and some of the lessons to be learned....As I listen to you talk, it seems to me that one can point to a number of serendipitous events where if things had not been done, captopril probably wouldn't have been discovered. Let me just tell you what some of those look like to me, and I would be interested in your thoughts. First, of course, if you hadn't worked with Dr. Deulofeu, the likelihood is that you would not have been invited to come to the United States.

Ondetti: Yes. Almost certainly that's the case.

Rosenberg: Second, if you had not been asked to go to work on peptides, even if you didn't like it, you would not have learned the tools of the trade which would have enabled you to recognize how to synthesize peptides and how peptides might be degraded. Do you think that's right?

Ondetti: Oh, yeah, that is quite correct. I think that if I would have had my choice of working in steroids, I would probably never have been asked to collaborate on converting enzyme.

Rosenberg: So a third point is that when John Vane was able to excite Dave Cushman about the snake venom, Dave obviously needed a collaborator where the biology and the chemistry could be coupled and the two of you guys had to be willing to work together for this to proceed. Isn't that right?

Ondetti: Yeah, that is true. Dave had come to the Institute like a year before, and I knew that he was working on some type of enzymes that were fluorinating compounds, but we never had a chance to interact. But we were asked, I guess by the powers that be, I guess Dr. Smith and Welch and Zola had decided that we had to work together and it came out very naturally. We had different backgrounds, but we were sort of attuned to each other's research needs. He was a biochemist, and I was a chemist, so from the very beginning we had a very close collaboration and not only among ourselves, but also with the rest of the pharmacology department. Because Zola had sort of taken over Dave's lab that was in the department of biochemistry, but he had asked David to move to pharmacology, and David was happy to oblige. So we had this collaboration with pharmacology with the isolated smooth muscle testing and the biochemistry and the chemistry. I think that was critical.

Rosenberg: And I guess you know, one can say that the environment in the company at that time was also very important. You have mentioned Zola Horovitz a number of times. Zola had to be supportive. At moments I'm sure he had to run interference for this activity. So he had to believe in the importance of the science, even when it was completely unproven in terms of concept because, as you pointed out, there was no precedent for this sort of work. So it seems to be there are a number of moments and a number of critical people, and it makes for a great story, as well as a great discovery.

Ondetti: Yeah, I think many times we don't realize how important is the particular environment, not necessarily only in terms of having people of the right intellectual capability, but people who are fired by something that is different, something that is new, something that gives you the possibility of making a contribution, a research contribution. And that is very critical in a pharmaceutical endeavor. Zola came to the company, actually, to do research because he was supposed to be having a lab on CNS research and slowly, because of his personality, he was drawn into more of a managerial function because he could get along with people. He was always very keen in supporting people who had projects that had a great basic research impact.

Rosenberg: So Zola understood that at the end of the day, the quality of the people determines the direction and the success of the company.

Ondetti: It is not necessarily only that you pick a project because it has at the end a dollar sign in terms of drugs that are known, but whether you are going to make a significant basic contribution. And he understood that. He was always supporting that. And he has, of course, a personality (that makes him) able to convince other people. He would always listen to them, and that was a great asset for us.

Rosenberg: Well, I guess what we all have to hope is that companies like Bristol-Meyers Squibb will continue to have an environment where outstanding science will be valued, even if it isn't clear at the outset—because it never is clear at the outset if you're really doing something original—where things will go.

Ondetti: Yes.

Rosenberg: Well, thank you, Miguel, very much.

Ondetti: Thank you very much.

Key Publications of Miguel Ondetti

Ondetti, M.A., and Thomas, P.L. (1965) Synthesis of a peptide lactone related to vernamycin B. J. Amer. Chem. Soc. 87: 4373.

Ondetti, M.A., Narayanan, V.L., Saltza, M. von, Sheehan, J.T., Sabo, E.F., and Bodansky, M. (1968) The synthesis of secretion. III. The fragment-condensation approach. J. Amer. Chem. Soc. 90: 4711.

Ondetti, M.A., Plusec, J., Sabo, E.F., Sheehan, J.T., and Williams, N. (1970) Synthesis of the cholecystokinin-pancreozymin. I. The C-terminal dodecapeptide. J. Amer. Chem. Soc. 92: 195.

Ondetti, M.A., Williams, N.J., Sabo, E.F., Plusec, J., Weaver, E.R. and Kocy, O. (1971). Angiotensin-converting enzyme inhibitors from the venom of Bothrops jararaca. Isolation elucidation of structure and synthesis.

Ondetti, M.A., Rubin, B., and Cushman, D.W. (1977) Design of specific inhibitors of angiotensin-converting enzyme: new class of orally active antihypertensive agents. J. Antibiotics 30: 765–759.

Ondetti, M.A., Condon, M.E., Reid, J., Sabo, E.F. Cheung, H.S., Cushman, D.W. (1979) Design of specific inhibitors of carboxypeptidases A and B. Biochemistry 18:1427–1430.