Institute of Pharmaceutical Chemistry, Goethe University Frankfurt/Main, Frankfurt, Germany.
J Pharmacol Exp Ther. 2012 Apr;341(1):68-80. doi: 10.1124/jpet.111.183947. Epub 2012 Jan 10.
Despite being a mainstay of inflammatory bowel disease (IBD) therapy, glucocorticoids (GCs) still carry significant risks with respect to unwanted side effects. Alternative drugs with a more favorable risk/benefit ratio than common GCs are thus highly desirable for the management of IBD. New and supposedly selective glucocorticoid receptor (GR) agonists (SEGRAs), with dissociated properties, have been described as promising candidates for circumventing therapeutic problems while still displaying full beneficial anti-inflammatory potency. Here, we report on compound A [CpdA; (2-((4-acetophenyl)-2-chloro-N-methyl)ethylammonium-chloride)] and N-(4-methyl-1-oxo-1H-2,3-benzoxazine-6-yl)-4-(2,3-dihydrobenzofuran-7-yl)-2-hydroxy-2-(trifluoromethyl)-4-methylpentanamide (ZK216348), two GR agonists for the treatment of experimental colitis. Their therapeutic and anti-inflammatory effects were tested in the acute trinitrobenzene sulfonic acid-mediated colitis model in mice against dexamethasone (Dex). In addition to their influence on immunological pathways, a set of possible side effects, including impact on glucose homeostasis, steroid resistance, and induction of apoptosis, was surveyed. Our results showed that, comparable with Dex, treatment with CpdA and ZK216348 reduced the severity of wasting disease, macroscopic and microscopic damage, and colonic inflammation. However, both SEGRAs exhibited no GC-associated diabetogenic effects, hypothalamic pituitary adrenal axis suppression, or development of glucocorticoid resistance. In addition, CpdA and ZK216348 showed fewer transactivating properties and successfully dampened T helper 1 immune response. Unlike ZK216348, the therapeutic benefit of CpdA was lost at higher doses because of toxic apoptotic effects. In conclusion, both SEGRAs acted as potent anti-inflammatory agents with a significantly improved profile compared with classic GCs. Although CpdA revealed a narrow therapeutic window, both GR agonists might be seen as a starting point for a future IBD treatment option.
尽管糖皮质激素（GCs）是炎症性肠病（IBD）治疗的主要药物，但它们仍存在严重的不良反应风险。因此，对于 IBD 的治疗，人们非常希望能够使用其他药物来替代普通 GCs，这些药物具有更好的风险/效益比。具有分离特性的新型和据称选择性糖皮质激素受体（GR）激动剂（SEGRAs）已被描述为有希望的候选药物，可以规避治疗问题，同时仍保持充分的抗炎疗效。在这里，我们报告了化合物 A [CpdA；（2-（（4-乙酰基苯基）-2-氯-N-甲基）乙基氯化铵）]和 N-（4-甲基-1-氧代-1H-2,3-苯并恶嗪-6-基）-4-（2,3-二氢苯并呋喃-7-基）-2-羟基-2-（三氟甲基）-4-甲基戊酰胺（ZK216348），这两种 GR 激动剂用于治疗实验性结肠炎。在小鼠三硝基苯磺酸介导的结肠炎模型中，用它们来对抗地塞米松（Dex），测试了它们的治疗和抗炎作用。除了对免疫途径的影响外，还调查了一组可能的副作用，包括对葡萄糖稳态、类固醇耐药性和细胞凋亡诱导的影响。我们的结果表明，与 Dex 相比，用 CpdA 和 ZK216348 治疗可减轻消瘦病、宏观和微观损伤以及结肠炎症的严重程度。然而，这两种 SEGRAs 都没有表现出 GC 相关的致糖尿病作用、下丘脑-垂体-肾上腺轴抑制或糖皮质激素耐药性。此外，CpdA 和 ZK216348 显示出较少的转录激活特性，并成功抑制了辅助性 T 细胞 1 免疫反应。与 ZK216348 不同，CpdA 的治疗益处由于毒性凋亡作用而在较高剂量时丧失。总之，与经典 GCs 相比，这两种 SEGRAs 都具有较强的抗炎作用，且具有显著改善的特性。虽然 CpdA 显示出较窄的治疗窗口，但这两种 GR 激动剂都可能成为未来 IBD 治疗选择的起点。
