From Snake Venom to Medicine: How Miguel Ondetti Co-Created Captopril

The National Inventors Hall of Fame^® is filled with stories of inventions that have been influenced by nature. Among these is the story of captopril. The first of a new class of drugs known as angiotensin converting enzyme (ACE) inhibitors, captopril is highly effective in treating hypertension, or high blood pressure.

According to the Centers for Disease Control and Prevention, nearly 120 million American adults have high blood pressure. That’s more than 48% of our country’s adult population. While many people depend on medications to manage their blood pressure, they might not know the origins of these important drugs. For instance, how many people might be aware that a viper's venom led to a breakthrough in blood pressure medication?

Read on to uncover the story behind captopril as you learn about one of its co-creators, National Inventors Hall of Fame^® Inductee Miguel Angel Ondetti.

A Team With a Goal

Ondetti was born in Buenos Aires, Argentina, in 1930. He studied at the University of Buenos Aires School of Sciences, earning his doctorate in chemistry in 1957. The same year, he joined Squibb (now Bristol-Myers Squibb Co.) as a senior research chemist at the Squibb Institute in Buenos Aires. In 1960, he was offered a position with Squibb in the U.S.

Reflecting on his decision to accept this position, Ondetti said, “I felt that I had found my niche in which I could work in collaboration, not only with chemists, but […] also with biologists. That was very important to me.”

It was at Squibb that Ondetti began collaborating with his colleague and fellow National Inventors Hall of Fame Inductee David Cushman. Together, Ondetti and Cushman began exploring what scientists had previously discovered about the venom of a Brazilian pit viper.

In 1968, studies performed at the Royal College of Surgeons of England had shown that nontoxic peptides found in the viper’s venom inhibited the production of angiotensin II, which causes narrowing of the blood vessels and increased blood pressure.

Initial studies had been done with synthetic compounds that mimic the ACE inhibitors in the venom, but those compounds proved to be effective only when administered by injection. This had ruled them out for a chronic condition like high blood pressure, for which pills were preferable because patients would need to take the medication throughout their lives.

Could an effective drug be produced in pill form? Through persistent problem solving, Ondetti and Cushman would answer this question.

A Breakthrough Medication

After years of trying to make the drug in pill form, Ondetti and Cushman made a breakthrough in 1974. Working together at the Squibb Institute for Medical Research, they applied their understanding of the enzyme structure and developed rapid methods to identify orally active ACE inhibitors. With this approach, the colleagues ultimately identified, purified and synthesized the key substance, captopril.

Marketed as Capoten, it was the first medical treatment to establish angiotensin's role in high blood pressure, and it opened a new field of medical research: ACE inhibition.

"When we first discovered the compound, we had no idea of its clinical applications," Ondetti said. "Capoten really was the first example of rational drug design based on a hypothetical biological mechanism."

A derivative of only two amino acids, captopril is “one of the simplest, yet one of the most optimized of any drug ever taken by patients.” It was the first instance of scientists applying a 3D protein structure to design a drug, which would lead to the structure-based drug design that is now used throughout the pharmaceutical industry.

Captopril lowered blood pressure with fewer negative side effects than earlier treatments, improving patients' quality of life while increasing the likelihood that they would continue taking the medication as prescribed. Captopril also has been found to significantly reduce the rate of death among patients with congestive heart failure, and it can help prevent kidney failure in patients with diabetes.

Ondetti retired as Bristol-Myers Squibb’s senior vice president for cardiovascular and metabolic diseases in 1991. During his 34-year career at the company, he had earned more than 100 patents.

In 1991, Ondetti was awarded the Perkin Medal, and in 1999, he and Cushman received the Lasker Award. Also in 1999, Bristol-Myers Squibb was awarded the National Medal of Technology, the nation's highest honor for technological innovation, due in part to Ondetti and Cushman’s development of captopril. In 2007, both Ondetti and Cushman were inducted into the National Inventors Hall of Fame.

Meet More World-Changing Inventors

Ondetti is one of more than 600 inspiring creators, innovators and entrepreneurs who have been inducted into the National Inventors Hall of Fame. To learn more of these inventors’ unique stories, keep exploring our website.