The Discovery of Captopril: a reply Charles G. Smith and John R. Vane We appreciate the opportunity to comment on the replies of Drs. Gavras and Erdos ( FASEB J. <h3>18</h3>, 225–226, 2004) to our editorial, "The Discovery of Captopril" ( FASEB J. <h3>17</h3>, 788–789, 2003). Our article focused totally and solely on the discovery of captopril per se and not on the discovery of the angiotensin-converting enzyme (ACE) or its role in human disease, discussed by Drs. Gavras and Erdos. As is the case in many areas of biomedical research, the underlying biochemical mechanisms were discovered using funding from the U.S. government, in addition to various philanthropic sources. When a conception by an inventor focuses on a specific, novel compound that affects a targeted metabolic pathway in such a way that a previously unseen and desirable therapeutic result is achieved, with no government money involved in that discovery, the product that results is owned by the inventor, as should be the case. It must be noted that the synthesis of a peptidomimetic by converting an orally inactive peptide (in this case, teprotide) to an orally active compound (captopril) had not been, to our knowledge, successfully accomplished at the time Squibb did its work. We agree completely with the history noted by Drs. Gavras and Erdos with respect to their work and that of Dr. John Laragh and others in demonstrating a role for the renin-angiotensin system in hypertension. Nonetheless, as noted in our article, only two of some dozen hypertension experts CGS personally contacted in the late 1960s to the early 1970s stated they believed an ACE inhibitor would be therapeutically useful in the treatment of so-called "essential" hypertension. Dr. Laragh, an expert in this field who had already shown the benefits of blocking the renin-angiotensin-aldosterone axis with a ß blocker (1972–1973) and with the octapeptide Ang II receptor blocker saralasin (1973–1974), was Squibb’s primary clinical consultant at the time and he strongly supported the idea of searching for an orally active ACE inhibitor. Dr. James Knill, Squibb’s V.P. for Medical Affairs, did not find it an easy task to recruit the number of physicians needed to conduct the NDA program that led to FDA approval. We submit that this demonstrates a definite naiveté among experts treating hypertension at that time with respect to the role of an ACE inhibitor in treating "essential" hypertension. Dr. Zola Horovitz, Associate Director, Squibb Institute for Medical Research, agrees with our original representations and with this commentary. With respect to the question of government support in the discovery of successful drugs, the reader is referred to a Tufts Center for the Study of Drug Development white paper entitled "Public and Private Sector Contributions to the Discovery and Development of ‘Impact’ Drugs," by J. M. Reichert and C. P. Milne, dated May, 2002. This white paper offers a very interesting perspective on approaches to comparing industrial and academic contributions to the discovery of new drugs. Dr. Erdos appropriately criticizes our failure to include Prof. Arnold Welch in the original article. Arnold was very influential in various stages of both our careers and was, indeed, a great man of biomedical science and medicine. We do regret this unfortunate oversight. Respectfully,

/lp/fed-of-american-socs-for-experimental-biology/the-discovery-of-captopril-a-reply-OalYLVOsyB