Mineralocorticoid receptor antagonists: The evolution of utility and pharmacology

For more than 30 years after the discovery of aldosterone. scientists belie ved that its sole site of action was at epithelial tissues, most notably th e kidney, where it mediated the transport of Na and K. It was soon recogniz ed aldosterone contributed to several diseases by causing edema. Armed with this information. scientists set out more than 30 years ago to develop an antagonist of the mineralocorticoid receptor for the treatment of edematous states. From this effort, spironolactone (Aldactone(R)) was discovered. Sp ironolactone acts functionally as a competitive inhibitor of the mineraloco rticoid (aldosterone) receptor, and although spironolactone is an effective mineralocorticoid receptor antagonist, it is not without limitations. Thes e limitations include unwanted progestational and antiadrogenic side effect s that limit its use in the chronic treatment of disease. In addition to it s actions at the collecting tubule, aldosterone can participate in pathophy siology by actions at the heart, vasculature, and kidney, and it is likely that the most significant contributions to cardiovascular disease are due t o actions at these sites rather than those related to Na and water retentio n. This is underscored by the recent clinical results from the RALES-004 Tr ial in which treatment with Aldactone demonstrated a significant benefit on mortality in patients with severe heart Failure. The limited utility of sp ironolactone owing to the aforementioned steroid-related side effects has b een especially frustrating, given the newly recognized role of aldosterone in cardiovascular disease. To obviate these limitations, eplerenone is curr ently being developed by Searle. Eplerenone is a competitive antagonist of the mineralocorticoid receptor that takes advantage of replacing the 17 alp ha-thoacetyl group of spironolactone with a carbomethoxy group, conferring excellent selectivity for the mineralocorticoid receptor over other steroid receptors. The pharmacological profile of eplerenone positions it to be an effective and selective minetalocorticoid receptor antagonist.