History of Heart Failure

“…On the afternoon of Wednesday, March 13, 1974, we got together to discuss a paper by Byers and Wolfenden that had been published a year earlier… it described ‘L’-benzylsuccinic acid, by far the most potent inhibitor of carboxypeptidase A that had ever been developed. The authors, in a somewhat theoretical exercise, ascribed the potent inhibitory activity of this compound to the fact that it was a ‘biproduct analog’ that combined, in a single molecule, binding interactions characteristic of both products of the enzyme’s action. The majority of the compound’s structure was analogous to an aromatic amino acid product, with only a single succinyl carboxyl group taken to be analogous to the corresponding, newly liberated carboxylic acid function of the second hydrolytic product. It was widely known how an amino acid product would bind to the active site of carboxypeptidase A, but what about this succinyl carboxylate? Byers and Wolfenden discussed but dismissed rather too easily the suggestion that the carboxylate function might bind to the catalytically functional zinc ion present at the active site of this well-characterized peptidase; however, in our discussion, we did not at all dismiss this important possibility. A number of properties of ACE suggested to us that it too was an exopeptidase with an active site similar to that of carboxypeptidase A, presumably including the presence of a zinc ion, although this had not yet been directly demonstrated. The major difference between the two exopeptidases, we thought, was that the active site of ACE had evolved to accommodate a dipeptide residue rather than a single amino acid residue as the leaving group for the peptidolytic reaction that it catalyzed. With this simple hypothetical model in mind, instead of a substituted succinic acid derivative, we envisaged, as an inhibitor of ACE, a similar compound extended by the addition of an amino acid residue, a substituted succinyl amino acid derivative. Benzylsuccinic acid is an analogue of the amino acid phenylalanine, which, as a terminal amino acid of a peptide substrate or as a product, binds very effectively to the active site of carboxypeptidase A. Since we needed an analogue of a dipeptide that would bind effectively to ACE, Ala-Pro was the obvious choice from our studies with the B. jararaca peptides. The compound suggested from such deliberations was D-2-methylsuccinyl-Lproline, although we decided to first make the much simpler molecule succinyl-L-proline, an analogue of the dipeptide Gly-Pro. From this moment of conception on March 13, 1974, only a year and a half passed before the first synthesis of captopril….”1 This narrative by Cushman and Ondetti demonstrates step by step the conceptual framework that led to the discovery of captopril. The authors read a paper that demonstrated that there was a new potent and specific inhibitor of carboxypeptidase A, an enzyme that is important in the gastrointestinal system. Cushman and Ondetti immediately saw that it might be possible to design an analogous simple chemical compound that might be a specific inhibitor of the angiotensin-converting enzyme (ACE), which they felt sure was an enzyme very similar in structure to the much better–characterized carboxypeptidase A. This time they took a different approach that proved essential to their subsequent success. Instead of concentrating on the structure of agents that could inhibit ACE, they directed their attention to the structure of the ACE—a structure that was not actually known, but which had been hypothesized on the basis of its probable similarity to carboxypeptidase A. When they received the Lasker Award, Cushman and Ondetti observed: “Although understanding the relationship between the structure of teprotide and its biological activity was important to the eventual development of captopril, the key point of our new design strategy was the shift in focus from the inhibitor to the enzyme” (http://www.laskerfoundation.org/awards/1999_c_description.htm). Thus, they began constructing agents that, because of their molecular structures, were likely to bind to the active site on ACE in a manner similar to the binding of the potent inhibitor of the analogous enzyme carboxypeptidase A. Captopril entered clinical trials in 1977 and was approved by the Food and Drug Administration in 1981.