The future of angiotensin-converting enzyme inhibitors.
After a brief introduction summarizing their historical development and the classification of angiotensin-converting enzyme inhibitors by chemical structure, the considerations involved in developing new and improved drugs of this pharmacologic class are discussed. These include properties such as the drug's potency, route of absorption and excretion, pharmacokinetics, drug disposition, and toxicity. Although increased potency, a traditional method for improving efficacy, can be achieved with angiotensin-converting inhibitors by introducing additional binding sites or by increasing the strength of binding at existing sites, safety testing has shown that with some compounds this approach may cause nephrotoxicity. Because renal disease is a common cause of hypertension and the two conditions frequently coexist, in some patients agents that are eliminated by both renal and hepatobiliary routes may be more desirable than those eliminated almost exclusively by the kidneys, such as captopril. This and other shortcomings of captopril have led to the development of two new angiotensin-converting enzyme inhibitors, zofenopril and fosfenopril, which are both in the early phase of clinical investigation. The former is an analog of captopril and the latter is classified as a first phosphinic acid angiotensin-converting enzyme inhibitor. Another possibility for the future is the incorporation of two therapeutic objectives into a single compound in the form of an angiotensin-converting enzyme inhibitory diuretic which, although chemically feasible, may be of questionable practical value. Also, the success of blood pressure control through intervention at the level of the renin-angiotensin-aldosterone system has created interest in the development of renin inhibitors. The primary stimulus for this avenue of investigation was the specificity of renin, which has only one substrate while converting enzyme has many.