David W. Cushman
Born in Indianapolis, IN
(November 15, 1939 – August 14, 2000)
Years of Discovery 1967 - 1981

An Enzymologist Discovers a Whole New Class of Blood Pressure Medicine

A poor Indiana boy, David Cushman received a PhD in Biochemistry at the University of Illinois, then moved east to New Jersey to land at the Squibb Institute for Medical Research, where he would transform chemicals into a whole new class of hypertension drugs.

After various projects, it was suggested he study the Brazilian pit viper’s venom, a common, but lethal snake in Southeastern Brazil. Something in its venom inhibited an enzyme, ACE to lower blood pressure. He jumped at the chance, recalling, “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.”

Beginning in the 1950s insurance companies noticed that hypertension, aka high blood pressure correlated with shorter lifespans. Then the Framingham Heart Study showed that high blood pressure correlated with cardiac events. Hypertension was known as the silent killer because there were rarely any symptoms. But there were catastrophic results – heart attacks and strokes. Decade after decade, studies showed that lowering blood pressure to normal levels increased lifespans by delaying heart attacks, strokes, and other maladies.

In looking for drugs to lower blood pressure, an early hypothesis was that the kidney’s had some control over blood pressure through the renin-angiotensin system, involving the angiotensin converting enzyme (ACE). Along with a teammate Cushman would meet, their research would prove this true.

He ended up collaborating with a chemist originally from Argentina, Miguel Ondetti, to form the perfect team. Cushman says, “Our scientific backgrounds and approaches to problems were just different enough to be highly complementary. More importantly, we freely discussed and developed key ideas to such an extent that today we cannot always determine their precise origin.”

For six years they worked on the project, testing 2,000 reasonably diverse chemical structures for specific inhibition of ACE and found a small collection of metal binding compounds and other nonspecific agents. Some were interesting and they learned a lot about the enzyme, but nothing they found seemed to have commercial potential. So the company decided to stop the research on ACE inhibitors, going so far as to assign Ondetti to antibiotics.

Then on a March afternoon in 1974, reading literature involving peptides on ACE, Cushman had an epiphany. As Ondetti tells it, “When Dave saw that paper, it wasn’t that he believed that the compound was going to be an inhibitor of ACE, 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 (to proceed in that direction in their research).”

Ondetti goes on to say, “We didn’t officially seek permission or approval of the new 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 so that we didn’t have to actually report every single compound that we made.”

As Cushman tells it, this time rather than testing thousands of compounds, they tested compounds by design. In the next year, following a logical sequence designed to confirm the active site interactions they now proposed, they went through only 60 compounds before finding one with optimally effective binding. That compound achieved a remarkable 2,000-fold increase in ACE inhibitory potency! The drug – Captopril, turned out to have a quite simple chemical structures and to be one of the most optimized drugs to be studied for any indication at Squibb.

Ondetti says, “I guess we didn’t quite believe it until we had seen two key experiments. First of all, you could achieve inhibition of the ACE orally with a milligram and that was unheard of and very striking. And the second thing is that the key screen for antihypertensive agents were the spontaneously hypertensive rats. When we found that captopril was very potent on those rats, we knew that we had a very potent drug.”

Captopril proved to be the first of a whole new class of blood pressure drugs – the ACE inhibitors (ACEI). It is one of five types of drugs physicians use to lower patients’ blood pressure, lengthening and enhancing their lives. It was approved by the FDA in 1981 and it and it’s derivatives have become mainstays in the blood pressure medicines physicians prescribe. Captopril also is approved to treat heart failure and kidney disease.

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. All those things turned out to be true, but we didn’t know that at the time.
                                                                                                                                                       - David Cushman

For developing an innovative approach to drug design based on protein structure and using it to create the ACE inhibitors, powerful oral agents for the treatment of high blood pressure, heart failure, and diabetic kidney disease.

                                              - The Lasker Foundation upon awarding David Cashman and Miguel Ondetti the Lasker Award

David Cushman and Miguel Ondetti Receiving Their Lasker Awards
               America's Premier Medical Innovation Award

Links to More About the Scientist & the Science
Cushman and Ondetti’s Personal and Historical Perspectives
https://www.ahajournals.org/doi/pdf/10.1161/01.HYP.17.4.589
Lasker Award Including Interviews with Cushman and Ondetti
https://laskerfoundation.org/winners/ace-inhibitors-for-treating-hypertension/