Captopril, the first ACE inhibitor

In 1965 the Brazilian pharmacologist Sérgio Ferreira described a factor in the venom of the jararaca, a Brazilian pit viper, that strengthened the effects of bradykinin, a peptide that lowers blood pressure. Working with John Vane's laboratory in London, Ferreira showed that peptides in the venom also inhibited angiotensin-converting enzyme, or ACE, which makes angiotensin II, a peptide that narrows blood vessels and raises pressure.

At Squibb, the chemist Miguel Ondetti and his colleague David Cushman isolated peptides from the venom. One of them, a chain of nine amino acids called teprotide, proved an effective ACE inhibitor in patients, but it was too large to be absorbed when swallowed.

In March 1974 they read a paper by Byers and Wolfenden on an inhibitor of another enzyme, carboxypeptidase A. Drawing on it and on what was known of ACE's chemistry, they built a hypothetical model of its active site and designed molecules to fit it. They made and tested about 100 compounds before synthesizing captopril, a proline derivative carrying a sulfhydryl group, in October 1975. Their 1977 report in Science showed that the new compounds blocked angiotensin I and lowered blood pressure in rats with renovascular hypertension when given by mouth.

Captopril entered clinical trials in 1977 and was approved by the Food and Drug Administration in 1981, sold as Capoten. It was later approved for congestive heart failure and, in 1994, as the first drug to prevent kidney disease in people with diabetes. In the SAVE trial, published in 1992, 2,231 patients with poor left ventricular function after myocardial infarction were randomized to captopril or placebo; after an average of 42 months, 20 percent had died on captopril and 25 percent on placebo. By 1999 nine other ACE inhibitors had been approved in the United States, and Ondetti and Cushman shared that year's Lasker clinical award.