Vanes team found that one of the venoms peptides selectively inhibited the action of angiotensin-converting enzyme (ACE), which was thought to function in blood pressure regulation; the snake venom functions by severely depressing blood pressure. During the 1970s, ACE was found to elevate blood pressure by controlling the release of water and salts from the kidneys. Captopril, an analog of the snake venoms ACE-inhibiting peptide, was first synthesized in 1975 by three researchers at the U.S. drug company E.R. Squibb & Sons Pharmaceuticals (now Bristol-Myers Squibb): Miguel Ondetti, Bernard Rubin, and David Cushman. Squibb filed for U.S. patent protection on the drug in February 1976, which was granted in September 1977, and captopril was approved for medical use in 1980. It was the first ACE inhibitor developed and was considered a breakthrough both because of its mechanism of action and also because of the development process. In the 1980s, Vane received the Nobel prize and was knighted for his work and Ferreira received the National Order of Scientific Merit from Brazil. The development of captopril was among the earliest successes of the revolutionary concept of ligand-based drug design. The renin–angiotensin–aldosterone system had been extensively studied in the mid-20th century, and this system presented several opportune targets in the development of novel treatments for hypertension. The first two targets that were attempted were renin and ACE. Captopril was the culmination of efforts by Squibbs laboratories to develop an ACE inhibitor.
Ondetti, Cushman, and colleagues built on work that had been done in the 1960s by a team of researchers led by John Vane at the Royal College of Surgeons of England. The first breakthrough was made by Kevin K.F. Ng in 1967, when he found  the conversion of angiotensin  I to angiotensin II took place in the pulmonary circulation instead of in the plasma. In contrast, Sergio Ferreira found bradykinin disappeared in its passage through the pulmonary circulation. The conversion of angiotensin I to angiotensin II and the inactivation of bradykinin were thought to be mediated by the same enzyme. In 1970, using bradykinin potentiating factor (BPF) provided by Sergio Ferreira, Ng and Vane found the conversion of angiotensin I to angiotensin II was inhibited during its passage through the pulmonary circulation. BPF was later found to be a peptide in the venom of a lancehead viper (Bothrops jararaca), which was a “collected-product inhibitor” of  the converting enzyme. Captopril was developed from this peptide after it was found via QSAR-based modification that the terminal sulfhydryl moiety of the peptide provided a high potency of ACE inhibition.Captopril gained FDA approval on April 6, 1981. The drug became a generic medicine in the U.S. in February 1996, when the market exclusivity held by Bristol-Myers Squibb for captopril expired.