The First ACE inhibitor: Captopril


The first ACE inhibitor!

Captopril (trade name Capoten), discovered in 1975 was Squibb’s first billion dollar drug and among the first drugs marketed as anti-hypertensive agents.

Discovery of captopril makes an interesting case of how a keen observation combined with systematic, rational drug design approach can lead us to some path breaking discoveries. A snake bite results in an instant drop of its prey’s blood pressure making its escape impossible! This fact was the initial lead for the discovery of captopril.

Let’s read on an interesting account of sequence of events and the thought process that went behind the success of captopril.

The story begins in late 1960s when S√©rgio Henrique Ferreira of Brazil, who had been studying the venom of a Brazilian pit viper, the jararaca (Bothrops jararaca), brings a sample of the viper's venom to John R. Vane,  the Professor of Experimental Pharmacology in the Institute of Basic Medical Sciences at the Royal College of Surgeons England. Ferreira had successfully isolated bradykinin potentiaing factor (BPF) from the snake venom. Vane was actively engaged in studying the cause of hypertension and was also a consultant to E. R. Squibb and Sons in New Brunswick. Ferreira had established that BPF potentiated the actions of bradykinin, probably by inhibiting the enzyme that inactivated it. At Vane’s request, BPF was tested on angiotensin converting enzyme (ACE) and found to be a potent inhibitor thereof. This led to Vane’s strong interest in ACE and its inhibition as a means of treating hypertension.

Ferreira and his colleague Greene isolated and characterized the first peptide, a bradykinin-potentiating pentapeptide that they called BPP5. This peptide also inhibited ACE and transiently lowered blood pressure in animal models.

Something about the ACE first. ACE is the abbreviation for angiotensin converting enzyme. ACE carries out conversion of Angiotensin I, a decapeptide to an octapeptide, angiotensin II.

 Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu                        Asp-Arg-Val-Tyr-Ile-His-Pro-Phe  

         Angiotensin  I                                                                                Angiotensin II




 Angiotensin II is a component of the renin-angiotensin-aldosterone system (RAAS). RAAS is a critical regulator of blood volume and systemic vascular resistance. While the baroreceptor reflex responds short-term to decreased arterial pressure, the RAAS is responsible for more chronic alterations. Renin, angiotensin II, and aldosterone act to elevate arterial pressure in response to decreased renal blood pressure, decreased salt delivery to the distal convoluted tubule, and/or beta-agonism. Through these mechanisms, the body can elevate blood pressure in a prolonged manner.

This means that if ACE is inhibited, angiotensin II, an important component of RAAS would become unavailable and thus is unable to raise the blood pressure.

Coming back to BPF, once it was determined that the peptides isolated from it were able to decrease the blood pressure by blocking the ACE enzyme, a detailed study of the enzyme and the mechanism behind its inhibition began.

The pentapeptide BPP5a, isolated by Ferreira because of its susceptibility to enzymatic degradation, displayed an effect that was very short lived in hypertensive animal models. However, another longer peptide, a nonapeptide isolated by David W. Cushman was found to be very stable.  Its name, teprotide, reflects the four proline residues that help to confer this stability. Teprotide was shown to be an effective antihypertensive drug, albeit one with limited use because of its expense and lack of oral activity. Many other peptides were synthesized and studied on in-vitro models.



Structure-activity studies with analogues of teprotide and BPP5a helped to refine a hypothetical model of the active site of ACE, a zinc metallopeptidase. The terminal sequence Trp-Ala-Pro of BPP5a, or the related but more stable sequence Phe-Ala-Pro, was found to be optimal for binding to the active site of ACE. However, being a peptide it lacked oral bioavailability and thus not a very suitable therapeutic candidate.

For this reason Squibb was about to drop the project. However, a couple of directors of the firm showed faith in the project and thus the hunt for ACE inhibitors continued.

Thousands of molecules were synthesized and tested for ACE inhibition but without success. A paper published on inhibition of an enzyme, carboxypeptidase A by L-benzylsuccinic acid provided the drug discovery team a sort of lead. Carboxypeptidase A is also a zinc containing exopeptidase similar to ACE. Considering the SAR of BPP5a, teprotide and other peptides showing inhibitory activity against ACE, the team in March 1973 decided to study the action of succinyl L-proline, an analogue of gly-pro.

Succinyl-L-proline displayed the properties of a specific ACE inhibitor and was orally active. However, it had very low potency to be considered as a drug candidate. This discovery stimulated the synthesis of the D-2-methyl derivative of succinyl-L-proline, which proved to be about 15 times more inhibitory than succinyl-L-proline, potent enough to demonstrate its oral activity for inhibition of the hypertensive actions of angiotensin I or augmentation of the hypotensive actions of bradykynin.


 Succinyl proline (selective but low potency)


D 2-Methyl succinyl proline

(improved oral bioavailability)


(introduction of –SH increases potency due to better interaction with active site)



 In a quest to enhance the interaction with the ACE active site, scientists tried replacing the carboxyl group with many other groups out of which hydroxamate and phosphonate groups were more effective than the succinyl carboxylate. However, when the carboxylate was replaced by a simple sulfhydryl function, a 2,000-fold increase in inhibitory potency was achieved. This molecule was named captopril. Captopril was introduced into the market in 1975, that is, aout a decade passes since the tests with BPF on ACE inhibition.

A great number of analogues of captopril were synthesized in various labs. A major class of specific ACE inhibitors reported a few years later were tripeptide analogues.  Out of these, enalpril and lisinopril by Merck made it to the market in 1980, just five years after the discovery of captopril. Both enalpril and lisinopril are prodrugs that lack sulfhydryl group. Both are esters that are hydrolysed in the gut to give the active forms of the drugs. All molecules discovered later are also prodrugs.

Presently, Indian market has the following orally acting ACE inhibitors: captopril, enalpril, lisinopril, ramipril, quinapril, perindopril, benazepril, imidapril, trandolapril, cilazapril and fosinopril.




Popular posts from this blog

Paracetamol: Drug Stories Part-III

Aspirin: Drug Stories Part-II