The History of Captopril

Captopril is an oral drug and a member of a class of drugs called angiotensin converting enzyme (ACE) inhibitors. Captopril is used to treat high blood pressure and heart failure. It decreases certain chemicals that tighten the blood vessels, so blood flows more smoothly and the heart can pump blood more efficiently.

Captopril(CAS.NO:62571-86-2) was developed in 1975 by three researchers at the U.S. drug company Squibb (now Bristol-Myers Squibb): Miguel Ondetti, Bernard Rubin and David Cushman. Squibb filed for U.S. patent protection on the drug in February 1976 and U.S. Patent 4,046,889 was granted in September 1977. Captopril gained FDA approval on April 6, 1981. The drug went generic in the U.S. in February 1996 as a result of the end of market exclusivity for Bristol-Myers Squibb.

The development of captopril was amongst the earliest successes of the revolutionary concept of ligand-based drug design. The renin-angiontensin-aldosterone system had been extensively studied in the mid-20th century and it had been decided that 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 Squibb's 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.

The development of captopril has been claimed as an instance of 'biopiracy' (commercialization of traditional medicines), since no benefits have flowed back to the indigenous Brazilian tribe who first used pit viper venom as an arrowhead poison.