Delyani J A
Searle Research and Development, St. Louis, Missouri, USA.
Kidney Int. 2000 Apr;57(4):1408-11. doi: 10.1046/j.1523-1755.2000.00983.x.
For more than 30 years after the discovery of aldosterone, scientists believed that its sole site of action was at epithelial tissues, most notably the kidney, where it mediated the transport of Na and K. It was soon recognized 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 was discovered. Spironolactone acts functionally as a competitive inhibitor of the mineralocorticoid (aldosterone) receptor, and although spironolactone is an effective mineralocorticoid receptor antagonist, it is not without limitations. These limitations include unwanted progestational and antiadrogenic side effects that limit its use in the chronic treatment of disease. In addition to its actions at the collecting tubule, aldosterone can participate in pathophysiology by actions at the heart, vasculature, and kidney, and it is likely that the most significant contributions to cardiovascular disease are due to actions at these sites rather than those related to Na and water retention. This is underscored by the recent clinical results from the RALES-004 Trial in which treatment with Aldactone demonstrated a significant benefit on mortality in patients with severe heart failure. The limited utility of spironolactone owing to the aforementioned steroid-related side effects has been especially frustrating, given the newly recognized role of aldosterone in cardiovascular disease. To obviate these limitations, eplerenone is currently being developed by Searle. Eplerenone is a competitive antagonist of the mineralocorticoid receptor that takes advantage of replacing the 17alpha-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 mineralocorticoid receptor antagonist.
在醛固酮被发现后的30多年里，科学家们认为其唯一的作用部位是上皮组织，最显著的是肾脏，在那里它介导钠和钾的转运。很快人们认识到醛固酮通过引起水肿导致多种疾病。基于这些信息，30多年前科学家们开始研发一种盐皮质激素受体拮抗剂用于治疗水肿状态。通过这项努力，螺内酯（安体舒通）被发现。螺内酯在功能上作为盐皮质激素（醛固酮）受体的竞争性抑制剂，虽然螺内酯是一种有效的盐皮质激素受体拮抗剂，但并非没有局限性。这些局限性包括不良的孕激素样和抗雄激素副作用，这限制了它在疾病慢性治疗中的应用。除了在集合管的作用外，醛固酮还可通过在心脏、血管系统和肾脏的作用参与病理生理过程，对心血管疾病的最重要影响可能是由于在这些部位的作用，而非与钠和水潴留相关的作用。这一点在RALES - 004试验的近期临床结果中得到了强调，在该试验中，安体舒通治疗对重度心力衰竭患者的死亡率显示出显著益处。鉴于醛固酮在心血管疾病中的新认识作用，由于上述与类固醇相关的副作用导致螺内酯的效用有限，这尤其令人沮丧。为了消除这些局限性，先灵公司目前正在研发依普利酮。依普利酮是盐皮质激素受体的竞争性拮抗剂，它利用用甲氧基羰基取代螺内酯的17α - 硫代乙酰基，赋予其对盐皮质激素受体相对于其他类固醇受体的优异选择性。依普利酮的药理学特性使其成为一种有效且选择性的盐皮质激素受体拮抗剂。
