Discovery and Optimization of <i>N</i>‑Acyl-6-sulfonamide-tetrahydroquinoline Derivatives as Novel Non-Steroidal Selective Glucocorticoid Receptor Modulators

Selective glucocorticoid receptor modulators (SGRMs), which can dissociate the transactivation from the transrepression of the glucocorticoid receptor (GR), are regarded as very promising therapeutics for inflammatory and autoimmune diseases. We previously discovered a SGRM HP-19 based on the passive antagonistic conformation of GR and bioassays. In this study, we further analyzed the dynamic changes of the passive antagonistic state upon the binding of HP-19 and designed and synthesized 62 N-acyl-6-sulfonamide-tetrahydroquinoline derivatives by structural optimization of HP-19. Therein, compound B53 exhibits the best transrepression activity (IC50 NF‑κB = 0.009 ± 0.001 μM) comparable with dexamethasone (IC50 NF‑κB = 0.005 ± 0.001 μM) and no transactivation activity. B53 can efficiently reduce the expression of inflammatory factors IL-6, IL-1β, TNF-α, and so on and makes a milder adverse effect and is highly specific to GR. Furthermore, B53 is able to significantly relieve dermatitis on a mouse model via oral drug intervention.选择性糖皮质激素受体调节剂（Selective glucocorticoid receptor modulators, SGRMs）能够解离糖皮质激素受体（glucocorticoid receptor, GR）的反式激活（transactivation）与反式抑制（transrepression）通路，被视为治疗炎症与自身免疫性疾病的极具潜力的候选疗法。本团队此前基于糖皮质激素受体的被动拮抗构象与生物实验，发现了一款选择性糖皮质激素受体调节剂HP-19。本研究进一步分析了HP-19结合后糖皮质激素受体被动拮抗状态的动态变化，并通过对HP-19的结构优化，设计并合成了62个N-酰基-6-磺酰胺四氢喹啉衍生物。其中，化合物B53展现出最优的反式抑制活性（NF-κB通路半最大效应浓度IC₅₀ = 0.009 ± 0.001 μM），其活性与地塞米松（NF-κB通路IC₅₀ = 0.005 ± 0.001 μM）相当，且无反式激活活性。B53可有效降低炎症因子IL-6、IL-1β、TNF-α等的表达水平，且不良反应更为温和，对糖皮质激素受体具有高度特异性。此外，通过口服给药干预，B53可显著缓解小鼠模型的皮炎症状。