Is there a future for renin inhibitors?

Abstract

Pharmacological interruption of the renin-angiotensin system is possible at three major sites, the angiotensin-converting enzyme (ACE), the AT1 receptor and at the interaction of renin with its substrate, angiotensinogen. Skeggs and his associates in 1957 argued logically but without prognostic accuracy that 'since renin is the initial and rate-limiting substance in the renin-angiotensin system, it would seem that the renin inhibition approach would be the most likely to succeed'. In fact, the development of agents that act at all three levels has enjoyed substantial success, yet renin inhibition, which showed early progress in studies in humans, has languished. Our task in this essay is to review the reasons for the slow evolution of renin inhibition and to discuss the potential of such agents in modern pharmacotherapy. All of the structure-action relationships have involved variation on the original peptide structure. The possibility that alternative approaches based on x-ray crystallography and reconstruction of the structure of the active site would lead to novel agents, appears not to have been explored systematically. This opportunity is all the more attractive because renin is one of the few targets that is actually soluble and amenable to x-ray crystallographic studies. At the moment, it appears that all renin inhibitor development programs have been closed, although hints periodically reappear to indicate that one company or another is pursuing a novel agent. The decision to close programs seems to have reflected not the therapeutic potential of renin inhibitors, but rather the cost of their synthesis, continuing problems with bioavailability and the remarkable success of the competitor class--the AngII antagonists. We believe that the potential of renin inhibition in human therapy has been under estimated and still shows substantial promise.