The Discovery Of ACE Inhibitors By Miguel Ondetti

Drug discovery is no easy feat and often involves a rollercoaster of successes and failures. This was no different in the case of Miguel Ondetti who travelled down a rocky road of research in organic chemistry to his final destination of hypertension treatment. Ondetti was an Argentinian citizen, born May 14th, 1930 in Buenos Aires, to Italian-immigrant parents. His father worked as both a craftsman and a night-watchman, whilst his mother cared for him at home. Despite his immigrant upbringing, Ondetti rose from a simple researcher to one of most iconic scientists today, through his studies of the renin-angiotensin system that would eventually bring about the discovery of ACE inhibitors.

During his younger years Ondetti worked as a bookkeeper and attended a vocational school for bookkeeping and accounting. This vocational education provided Ondetti with the necessary support for his future university work in the field of chemistry. Ondetti’s studies at the University of Buenos Aires ended in 1957 after his completion of a PDH on organic chemistry. By 1960, Ondetti moved from his dual role as teacher and researcher at the University of Buenos Aires and Buenos Aires Squibb Institute respectively, to a pure research career at The Squibb Institute for Medical Research in New Jersey. It was in New Jersey, that Ondetti began his research that would eventually lead him to the discovery of ACE (Angiotensin Converting Enzyme) inhibitors.

At the institute in 1960 Ondetti was broadly tasked to research peptide synthesis and potential endogenous, bioactive peptides. The goal of the research was to find either desirable or undesirable effects of peptides and thus utilise their agonistic or antagonistic nature, respectively, in the field of drug development. However, before Ondetti’s award winning research started, his first achievement was in fact focused on the gastrointestinal field, which provided the foundations for his future research regarding ACE inhibitors. After much research and testing he successfully synthesised a fully synthetic, bioactive form of secretin and cholecystokinin, drawing much attention to the growing field of peptide synthesis. This attention ultimately allowed him to continue in the field of peptide research and thus transfer to researching peptidases and the renin-angiotensin system. In 1968, Ondetti was invited to meet with John Vane and David Cushman to discuss laboratory results regarding the relationship between the venom from Bothrops jararaca and the conversion of angiotensin I to angiotensin II.

On a personal level, Ondetti was strongly drawn to this field of research due to his prior background in the same field of research in Argentina. Ondetti and his team started with great success through the synthesis of peptide sequences that produced inhibitory effects of the renin-angiotensin system and later confirmed that the most effective inhibitor of this system was in fact a nonapeptide that would later become known as teprotide. This was demonstrated through the antagonism of angiotensin I contractile activity and the agonism of contractile activity of bradykinin that is involved in vasodilation. Following the recent success, Ondetti attempted to separately find a new peptide inhibitor with a small amino acid sequence and maximum inhibitory effect. This was presented in the form of a tripeptide: Phe-Ala-Pro. However, in a very unfortunate circumstance, Ondetti was unable to modify this new peptide and further discovered that teprotide also had poor oral bioavailability. This forced teprotide to only be used only intravenously and Ondetti to revise his original research on the nonapeptide.

Following the successive failures, Ondetti was left with a small group operating to study peptide synthesis alongside studies of antibiotics due to the low probability of finding an orally active drug from the peptide field alone. However, due to Ondetti’s previous knowledge in peptide research, he jumped upon the opportunity of a benzyl succinic acid structure that was a potent inhibitor of carboxypeptidase A, ignoring further research into new antibiotics. Utilising past knowledge, he developed an alpha-methyl succinyl-L-proline molecule as a potential ACE inhibitor. Whilst initially displaying very poor results towards antagonistic effects on the renin-angiotensin system, it still had an agonistic effect on bradykinin contractile activity, similar to teprotide. Despite the lack of promise, Ondetti continued down the pathway of ACE inhibitors and after a series of modifications, he synthesised an alpha-D-methyl succinyl-L-proline molecule that expressed antagonistic effects on angiotensin I contractile activity and agonistic effects on bradykinin contractile activity. With now increasing promise and success, Ondetti conducted more testing and finally synthesised a 3-mercaptopropanoyl-L-proline molecule that was three thousand times more potent than the original succinyl-L-proline, with the addition of good oral bioavailability. This breakthrough molecule later became known as Captopril and was found to be ten times more active than teprotide.

The introduction of captopril led to the ability to treat various forms of hypertension. As an ACE inhibitor, captopril inhibits the action of Angiotensin Converting Enzyme, such that the enzyme cannot produce Angiotensin II from Angiotensin I. Along with the agonistic effect on bradykinin, this produces a vasodilatory effect and thus a reduced blood pressure as Angiotensin II cannot function to either vasoconstrict or stimulate aldosterone release, which could lead to an increased sodium retention and thus increased blood pressure. An overall decrease in blood pressure can be beneficial for conditions such a hypertension or Congestive Heart Failure (CHF) due to the decrease in arterial or vascular pressure and an increase in cardiac output. These effects decrease the workload on the heart and ability to supply blood and oxygen to all parts of the body, including the heart itself. Clinically, a single dose of captopril was found to increase cardiac output and reduce an overall high blood pressure in vascular networks. Tested alongside diuretics and digoxin, an overall decrease is observed in short-term signs, symptoms and survival of patients. Patients with congestive heart failure that received captopril treatments were found to have a higher exercise capability (tested on treadmill exercise) and expressed lesser symptoms/signs of shortness of breath (standing or sitting), fatigue and accumulation of fluid in any parts of the body. Furthermore, it was found that captopril treatments to individuals with left ventricular dysfunction (monitored over 3.5 years of treatment), reported a 19% reduction in overall mortality, 21% reduction in cardiovascular death and specifically a 25% reduction in cardiac infarctions.

These results, however, were not always present. Before the 1950s, we didn’t have many anti-hypertensive treatments that were of great success. In fact, in the 1940s, barbiturates and bromides were used as anti-hypertensive agents to simply support the patients rather than treat them. During this same period, Franklin D. Roosevelt died of a cerebral haemorrhage due to hypertension after being prescribed phenobarbital, massages and a low sodium diet named the Kempner diet. During the 1940s people relied on the Kempner diet of a low sodium intake and a low intake of meat, until Dr Edward D. Fries used pentaquine, an antimalarial drug, successfully as a hypotensive drug. From the 1950s onwards, more drugs were researched, but to a very shallow level of safety. Reserpine was produced and found to reduce blood pressure, but only later found to cause depression and suicide in patients. The introduction of captopril provided much relief from simple diets and unsafe drugs. Furthermore, captopril is orally bioavailable and provides a far more convenient alternative to teprotide, that could only be used in emergency situations due to its intravenous administration. In combination with the newly introduced diuretics and beta-blockers such as propranolol, captopril helped reduce blood pressure to desired levels “in more than 50% of patients”, thus demonstrating a clear clinical benefit.Further discovery, research and development in the field of hypertension allowed rival companies to improve the original formula, making second or third generation analogues such as enalapril, that didn’t produce as many side effects and required lesser dosing frequencies. Whilst we acknowledge the works of Tigerstedt and Bergman for their contribution to the renin-angiotensin system, Ondetti’s synthesis of ACE inhibitors drove our understanding and commitment to further research into regulation of the renin-angiotensin system. Subsequently, we have now progressed further into the system’s regulation via the synthesis of Angiotensin I or Angiotensin II receptor inhibitors and even Direct Renin Inhibitors. Such discoveries provide multiple alternatives and multiple levels of selectivity for patients to utilise in order to treat their own specific cases of disease.

The works of Miguel Ondetti, from researcher to iconic scientist, have propelled forward research in the field of hypertension and other cardiovascular diseases. The discovery of ACE inhibitors allowed us to understand the renin-angiotensin system and thus treat patients by regulating various steps or components involved. From dietary change to multiple generations of drugs, we must acknowledge the struggles of this iconic pioneer as we reap the ongoing fruits of his initial discovery.