Schäcke Heike, Berger Markus, Rehwinkel Hartmut, Asadullah Khusru
Bayer Schering Pharma AG, Global Drug Discovery, TRG Inflammation/Immunology, Müllerstr. 178, 13342 Berlin, Germany.
Mol Cell Endocrinol. 2007 Sep 15;275(1-2):109-17. doi: 10.1016/j.mce.2007.05.014. Epub 2007 May 31.
Glucocorticoids are among the most successful therapies in the treatment of chronic inflammatory and autoimmune diseases. Their efficacy seems to be caused by the interference of the ligand-activated glucocorticoid receptor with many pro-inflammatory pathways via different mechanisms. The ubiquitous expression of the glucocorticoid receptor is a prerequisite for efficacy. Their main drawback, however, is due to their potential to induce adverse effects, in particular upon high dosage and prolonged usage. For the purpose reducing systemic side effects, topical glucocorticoids that act locally have been developed. Nevertheless, undesirable cutaneous effects such as skin atrophy persist from the use of topical glucocorticoids. Therefore a high medical need exists for drugs as effective as glucocorticoids but with a reduced side effect profile. Glucocorticoids function by binding to and activating the glucocorticoid receptor which positively or negatively regulates the expression of specific genes. Several experiments suggest that negative regulation of gene expression by the glucocorticoid receptor accounts for its anti-inflammatory action. This occurs through direct or indirect binding of the receptor to pro-inflammatory transcription factors that are already bound to their regulatory sites. The positive action of the receptor occurs through homodimer binding of the ligand receptor complex to discrete nucleotide sequences and this contributes to some of the adverse effects of the hormone. Glucocorticoid receptor ligands that promote the negative regulatory action of the receptor with reduced positive regulatory function should therefore show an improved therapeutic index. A complete separation of the positive from the negative regulatory activities of the receptor has so far not been possible because of the interdependent nature of the two regulatory processes. Nevertheless, recent understanding of the molecular mechanisms of the GR has triggered several drug discovery programs and these have led to the identification of dissociated GR-ligands. Such selective GR agonists (SEGRAs) are likely to enter clinical testing soon.
糖皮质激素是治疗慢性炎症和自身免疫性疾病最成功的疗法之一。它们的疗效似乎是由配体激活的糖皮质激素受体通过不同机制干扰许多促炎途径所致。糖皮质激素受体的普遍表达是其发挥疗效的前提条件。然而，它们的主要缺点是有可能诱发不良反应，尤其是在高剂量和长期使用时。为了减少全身副作用，已开发出局部起作用的外用糖皮质激素。然而，外用糖皮质激素的使用仍会出现诸如皮肤萎缩等不良皮肤反应。因此，迫切需要像糖皮质激素一样有效但副作用更小的药物。糖皮质激素通过与糖皮质激素受体结合并激活该受体来发挥作用，该受体对特定基因的表达起正向或负向调节作用。多项实验表明，糖皮质激素受体对基因表达的负向调节作用是其抗炎作用的原因。这是通过受体直接或间接与已结合到其调控位点的促炎转录因子结合来实现的。受体的正向作用是通过配体 - 受体复合物的同二聚体与离散的核苷酸序列结合而发生的，这导致了该激素的一些不良反应。因此，能够促进受体的负向调节作用而减少正向调节功能的糖皮质激素受体配体应具有更好的治疗指数。由于这两种调节过程相互依存的性质，迄今为止，受体的正向和负向调节活性还无法完全分离。尽管如此，最近对糖皮质激素受体分子机制的了解引发了多个药物研发项目，这些项目已导致鉴定出解离型糖皮质激素受体配体。这类选择性糖皮质激素受体激动剂（SEGRAs）可能很快会进入临床试验。
