Captopril is an ACE inhibitor used for the treatment of hypertension and some types of chronic heart failure. Captopril was the first ACE inhibitor developed and was considered a breakthrough both because of its novel mechanism of action and also because of the revolutionary development process. It is marketed by Bristol-Myers Squibb under the trade name Capoten®.

Development of captopril

The development of captopril was amogst the earliest successes of the revolutionary concept of structure-based drug design. The renin-angiontensin-aldosterone system had been extensively studied in the mid-20th century and it had been decided that this system presented several opportune targets in the development of novel treatments for hypertension. The first two targets that were attempted were renin and ACE.

Captopril was the culmination of efforts by Squibb's laboratories (now Bristol-Myers Squibb) to develop an ACE inhibitor. Captopril was developed from a lead molecule which was a collected-product inhibitor of ACE. Importantly, through QSAR-based modification, it was found that the terminal sulfhydryl-moiety provided a high potency of ACE inhibition.

Shortcomings

During Phase III/IV trials of captopril, it was found that captopril had some undesirable adverse effects. The most predominant of which included cough, rash and taste disturbances (metallic or loss of taste). Cough is an adverse effect common to all of the ACE inhibitors, but the rash and taste disturbances were attributed to the very sulfhydryl moiety which granted captopril its potency.

An additional shortcoming of captopril is the short half-life, necessitating 2-3 times daily dosing.

The development of longer-acting ACE inhibitors lacking the sulfhydryl-moiety such as enalapril proved to be the downfall of captopril and, whilst it is still used, it is no longer amongst the more widely used ACE inhibitors.