The Discovery of Captopril

CHARLES G. SMITH AND JOHN R. VANE Over the past few years, and particularly recently, there has been a goodly amount of discussion in the press about the discovery and development of highly successful drugs by the pharmaceutical industry, in which extensive data generated by government-sponsored research is claimed to have played a signicant role in the industrys success. Detailed analysis of these claims (1) has concluded that the concept of major monetary input into such drugs by the government is not justied. Indeed, the Tufts group nds that undue weight has been given to government contributions by parties making such analyses because their approach is to compare the number of publications in a certain eld emanating from academia and NIH with publications from the drug companies. The difference in favor of the NIH should not be surprising since we know that academia and NIH live by publishing while the industry holds back publication until its intellectual property is adequately protected by patenting. Since we were both closely afliated with the discovery and development of captopril, one of the compounds on the above-mentioned list of drugs (1) in which government funding is claimed to have played a major role, we believe that the history of the development of this important drug should become a matter of public record, since we know of no government money involved therewith. We also challenge the people who state that government money was involved, to justify their claims with factual data other than publications. of England. He was also a consultant to E. R. Squibb and Sons in New Brunswick, N.J. Charles G. Smith was the V.P. for R&D at Squibb. Vane presented to the Squibb research staff the concept of the importance of ACE as a major regulator of blood pressure. At that time, ACE was known to play a role in so-called malignant hypertension (a life-threatening, rapid escalation of blood pressure). Since this condition represents only 5% of hypertensive disease and effective medications were available for that indication, it was not considered to be a viable commercial target. Vanes careful analysis of the probable role of the ACE system in so-called essential hypertension was attractive to the Squibb research staff since, if he were correct, it would give the Company an opportunity to leap frog into the cardiovascular eld, in which it clearly wanted to be represented but had no good drug candidates in the pipeline. Embarking on a major research program aimed at the ACE system was no simple undertaking thirty years ago, since the majority of clinical experts in the eld at the time did not believe that ACE played a signicant role in essential hypertension. Smith called a dozen clinical experts to ask about their willingness to study a drug that inhibited ACE and only two expressed any interest. John Laragh, then a professor at Columbia University Medical School, expressed considerable interest. It must be emphasized that Vanes laboratory observations were made studying peptides from viper snake venom in vitro. Peptides are not absorbed when taken by mouth and must be injected to be effective in the animal body. Injection is not the preferred route of administration for the treatment of hypertension. In the early 1970s, no laboratory had succeeded in converting a peptide to a form that could be absorbed orally, but Squibbs concept was to test the hypothesis by investigating the snake venom peptide by injection and, if activity were demonstrated, then to tackle the problem of making an orally available form of the drug. Although Squibb scientists (especially David Cushman and Miguel Ondetti) eventually succeeded in accomplishing this unlikely feat, there was no road map for them to follow. Smith was not infrequently asked how R&D could justify spending the Companys hard earned money studying an injectable peptide that cost one million dollars per kilo to synthesize, for a drug that only Drs. Vane and Laragh had any condence might work. It is fair to say that Smiths consumption of antacids rose precipitously in defending the actions of the R&D group, particularly since he also had some doubts about the validity of the concept! Vanes lucid
0892-6638/03/0017-0788 FASEB

Development of the Concept In the 1960s, John R. Vane was actively investigating the cause of hypertension. During this time, a Brazilian post-doc, Sergio Ferreira, joined Vanes group and brought with him an extract bradykinin potentiating factor (BPF) of the venom of the Brazilian viper Bothrops jararaca. Ferreira had already established that BPF potentiated the actions of bradykinin, probably by inhibiting the enzyme that inactivated it. At Vanes request, BPF was tested on angiotensin converting enzyme (ACE) and found to be a potent inhibitor thereof. This led to Vanes strong interest in ACE and its inhibition as a means of treating hypertension.

Involvement of Squibb In the late 1960s and early 1970s, Vane was the Professor of Experimental Pharmacology in the Institute of Basic Medical Sciences at the Royal College of Surgeons
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deductions on the subject gave Squibb condence to proceed.

The Turning Point The most critical clinical test to be performed was to demonstrate, as had been done in animals, that the peptide would block the conversion of angiotensin I to II, the biochemical reaction mediated by ACE when administered intravenously to people. In such an experiment, angiotensin I or II is injected into an animal and both make the blood pressure rise. When the snake venom peptide was injected before the angiotensin, the blood pressure rose after angiotensin II but not after angiotensin I, as should be the case if ACE is inhibited in the body. When Squibb applied to the U.S. Food and Drug Administration (FDA) for permission to conduct this experiment in the United States, the FDA refused since angiotensin I was not marketed in this country (although angiotensin II was). As a result, Vane arranged to have the rst clinical test performed in the U.K. When the predicted inhibition of ACE was demonstrated in human beings in England, the FDA allowed Squibb to proceed in the United States by testing in patients with essential hypertension. Dr. Laragh, a strong supporter of the ACE concept, performed the initial clinical trial in the United States. As Smith recalls, he treated 17 patients with essential hypertension and the blood pressure came down in 14. This nding lead to a full-press, top priority effort at

Squibb to develop an orally active form of the drug, which Company scientists accomplished. Over the next decade, Squibb spent many millions of dollars on animal and clinical studies, formulations development, large scale production, etc., which lead to FDA approval in the early 1980s. Captopril (trade name Capoten) was Squibbs rst billion dollar drug and it opened a new approach for the treatment of this serious disease.

Use of Government Money? We know of no government money that went into any part of the discovery and development of this drug. We are very unhappy to have people with no direct knowledge of the history of captopril ponticating on the use of government money to discover and develop this product. The proponents of that theory should have to show some evidence, other than scientic publications in a general eld of research, to support their argument.

Reference
1. Reichert, J. M., and Milne, C.-P. (2002) Public and private sector contributions to the discovery and development of impact drugs. Tufts Center for the Study of Drug Development, Boston MA.

THE DISCOVERY OF CAPTOPRIL

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