Cardiology Research, Department Heart Diseases, Global Drug Discovery, Bayer Healthcare Pharmaceuticals, Wuppertal, Germany.
Mol Cell Endocrinol. 2012 Mar 24;350(2):310-7. doi: 10.1016/j.mce.2011.06.025. Epub 2011 Jul 13.
The blockade of mineralocorticoid receptors (MR) has been shown to be an invaluable therapy in heart failure and hypertension. To date, only two steroidal antimineralocorticoids, spironolactone (and its active metabolite canrenone) and eplerenone, have been approved, whereas novel non-steroidal compounds are in preclinical and early development. The careful investigation of the efficacy and tolerance of spironolactone in essential hypertension initially supported the idea that a more selective second generation of MR antagonists is desired for chronic treatment of cardiovascular diseases. More than 40 years went by between the approval of the first MR antagonist spironolactone and the market introduction of its sole successor, eplerenone. The molecular pharmacology of MR antagonists may be addressed at different levels. Available preclinical and clinical data of the two approved steroidal antimineralocorticoids allow a good comparison of potency and selectivity of MR antagonists and their pharmacokinetic properties. The search for novel generations of MR antagonists with the ultimate goal of a more tissue selective mode of action may require novel compounds that are differentiated with respect to the binding mode to the MR. Other factors that may contribute to tissue selectivity as e.g. the physicochemical properties of a drug and how they influence the resulting pharmacology in the context of tissue selective co-factor expression are even less well understood. In the following we will review these aspects and demonstrate that the molecular pharmacology of current MR antagonists is on the one hand far from well understood and, on the other hand, still offers room for improvements.
阻断盐皮质激素受体 (MR) 已被证明是心力衰竭和高血压治疗的宝贵方法。迄今为止，只有两种甾体类抗盐皮质激素，螺内酯（及其活性代谢物坎利酮）和依普利酮，已获得批准，而新型非甾体化合物则处于临床前和早期开发阶段。螺内酯在原发性高血压中的疗效和耐受性的仔细研究最初支持了这样一种观点，即需要更具选择性的第二代 MR 拮抗剂来慢性治疗心血管疾病。从第一个 MR 拮抗剂螺内酯获得批准到其唯一的后继者依普利酮上市，这期间过去了 40 多年。MR 拮抗剂的分子药理学可以在不同层面上进行研究。两种已批准的甾体类抗盐皮质激素的临床前和临床数据可很好地比较 MR 拮抗剂的效力和选择性及其药代动力学特性。寻找具有更具组织选择性作用模式的新一代 MR 拮抗剂可能需要新型化合物，这些化合物在与 MR 结合模式方面存在差异。其他可能有助于组织选择性的因素，例如药物的物理化学性质以及它们如何在组织选择性共因子表达的背景下影响药物的药理学，这些因素的了解程度就更低。在接下来的内容中，我们将回顾这些方面，并证明当前 MR 拮抗剂的分子药理学一方面远未被很好地理解，另一方面仍有改进的空间。
