Captopril Captopril (the generic name of the drug marketed as Capoten) is an ACE inhibitor, a drug that widens blood vessels and helps to relieve high blood pressure by blocking the production of the hormone angiotensin II.

The disease

High blood pressure, or hypertension, is a very common condition in which the arteries become too narrow. The blood is therefore pumped around the body too forcefully, making the heart work harder than necessary and putting strain on the artery walls. If left untreated, high blood pressure may result in permanent damage to the heart and circulatory system, as well as other organs, including the eyes, kidneys and brain.

Hypertensive patients thus have a substantially higher risk of stroke than people with normal blood pressure. The causes of high blood pressure are complex, and include both genetic factors and environmental variables like diet and stress. In Western countries, up to 25 per cent of the adult population may be affected by hypertension, and the incidence increases with age. While there is no cure for the condition, most cases can be managed with drugs.

The target

The major hormones controlling blood pressure are the angiotensins. Angiotensin I is a small peptide, containing just ten amino acids, which is cleaved off a circulating protein called angiotensinogen by the enzyme renin.

Another two amino acids are then removed by angiotensin-converting enzyme (ACE) to produce angiotensin II. This hormone causes muscles surrounding the blood vessels to contract very strongly; angiotensin II is therefore termed a vasoconstrictor.

The drug and how it works

Captopril is an example of an ACE inhibitor, a small molecule drug that binds to and inhibits angiotensin-converting enzyme. This prevents the conversion of angiotensin I into angiotensin II and thus helps to lower blood pressure.

Captopril is one of a range of commonly available ACE inhibitors, which also include benazepril, lisinopril and ramipril. These drugs may be given orally or intravenously. The oral drugs begin to work an hour or so after administration, while the intravenous drugs are active immediately.

How captopril was developed

The development of captopril is an interesting example of structure-based design, a strategy in which the structure of the target protein is used to help design the molecule that acts as its inhibitor.

In the case of captopril, the structure of the real target (angiotensin-converting enzyme) was not solved until very recently. The drug was therefore designed using a related enzyme called carboxypeptidase A, whose structure was assumed to be similar to the genuine target.

The first lead compound in this drug discovery process was called N-succinoylprolin and its inhibitory activity was very weak. By testing various different chemical structures based on the skeleton of N-succinoylprolin, the variant eventually named captopril was found to be 30 000 times more effective. Intriguingly, the structure of human ACE was solved recently and was shown to bear little resemblance to carboxypeptidase A.

Image credit: Anthea Sieveking