Molecule of the Month February 2016: Captopril

One of the most fascinating things about my sabbatical leave at the Liverpool School of Tropical Medicine a few years ago, was visiting the Hepetarium, which houses the Alastair Reed Snake Venom Research Unit headed up by Rob Harrison. The power of research into toxins, which has played a major role in the history of Biochemistry, Physiology and Medicine, in my view is often undervalued. But not in respect of the molecule of this month, captopril, the molecule that was introduced by the drug company Bristol Myers Squibb (then ER Squibb) as the first ACE inhibitor for the relief of hypertension. 

The structure of captopril is shown on the right, and it is know to act on angiotensin converting enzyme (ACE). The development of captopril, is a lovely example of how natural products can inform drug discovery. It is a result of a combination of Biological serendipity and incisive Chemistry. The original molecules associated with blood pressure modulation, extracted from venom, where too complex to be viable therapeutically. However, by first establishing the key role of the proline moiety in active site inhibition, the next phase was aimed at simplifying the peptidyl arm of the molecule.

The natural products associated with blood pressure modulating activity were peptides of the bradykinin family (brady-slow, kinin-movement related), including the nonapeptide, teprotide (LHS). As you can see from the final form of the drug, the enzyme anchor can be dramatically simplified, making the drug a real economic option. [As opposed to a synthetic nightmare!]. The systematic evaluation of variations on the natural product (structure-activity-relationships) led to captopril, as the first drug of this class. 

The simple active site inhibition model is shown schematically below. However, in order to address the many early reports of severe side effects, further refinement has led to a new generation of ACE inhibitors that include enalapril. There is a freely available summary of current ACE inhibitors here. The captopril story is an excellent example of how medicinal chemistry developed in the 1970s in particular. It was followed by approaches based on screening large automated libraries of compounds in a methodology called combinatorial chemistry. I note with interest and enthusiasm, the resurgence of Natural Product chemistry in the areas of antibiotics and anti-malarial drugs, and direct you to a nice review of this "renaissance" by Tadesz Molinski, which is free to download here.