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Discovery and Optimization of N-Acyl-6-sulfonamide-tetrahydroquinoline Derivatives as Novel Non-Steroidal Selective Glucocorticoid Receptor Modulators
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2022-11-18 , DOI: 10.1021/acs.jmedchem.2c01082 Dan Li 1 , Xiaodong Bao 2 , Jinping Pang 1 , Xueping Hu 3 , Longling Wang 4 , Jiajia Wang 4 , Zhaoxu Yang 4 , Lei Xu 5 , Siyu Wang 1 , Qinjie Weng 4 , Sunliang Cui 2 , Tingjun Hou 1, 6
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2022-11-18 , DOI: 10.1021/acs.jmedchem.2c01082 Dan Li 1 , Xiaodong Bao 2 , Jinping Pang 1 , Xueping Hu 3 , Longling Wang 4 , Jiajia Wang 4 , Zhaoxu Yang 4 , Lei Xu 5 , Siyu Wang 1 , Qinjie Weng 4 , Sunliang Cui 2 , Tingjun Hou 1, 6
Affiliation
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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 (IC50NF-κB = 0.009 ± 0.001 μM) comparable with dexamethasone (IC50NF-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.
中文翻译：
作为新型非甾体选择性糖皮质激素受体调节剂的 N-酰基-6-磺酰胺-四氢喹啉衍生物的发现和优化
选择性糖皮质激素受体调节剂 (SGRM) 可以将反式激活与糖皮质激素受体 (GR) 的反式抑制分离，被认为是非常有前途的炎症和自身免疫性疾病治疗药物。我们之前发现了基于 GR 和生物测定的被动拮抗构象的SGRM HP-19 。本研究进一步分析了HP-19结合后被动拮抗状态的动态变化，通过HP-19的结构优化设计合成了62N- acyl -6-sulfonamide-tetrahydroquinoline衍生物。其中，化合物B53表现出最好的反式抑制活性 (IC 50 NF-κB= 0.009 ± 0.001 μM）与地塞米松（IC 50 NF-κB = 0.005 ± 0.001 μM）相当，并且没有反式激活活性。B53能有效降低炎症因子IL-6、IL-1β、TNF-α等的表达，不良反应较轻，对GR具有高度特异性。此外，B53能够通过口服药物干预显着缓解小鼠模型的皮炎。
更新日期：2022-11-18
中文翻译：
作为新型非甾体选择性糖皮质激素受体调节剂的 N-酰基-6-磺酰胺-四氢喹啉衍生物的发现和优化
选择性糖皮质激素受体调节剂 (SGRM) 可以将反式激活与糖皮质激素受体 (GR) 的反式抑制分离，被认为是非常有前途的炎症和自身免疫性疾病治疗药物。我们之前发现了基于 GR 和生物测定的被动拮抗构象的SGRM HP-19 。本研究进一步分析了HP-19结合后被动拮抗状态的动态变化，通过HP-19的结构优化设计合成了62N- acyl -6-sulfonamide-tetrahydroquinoline衍生物。其中，化合物B53表现出最好的反式抑制活性 (IC 50 NF-κB= 0.009 ± 0.001 μM）与地塞米松（IC 50 NF-κB = 0.005 ± 0.001 μM）相当，并且没有反式激活活性。B53能有效降低炎症因子IL-6、IL-1β、TNF-α等的表达，不良反应较轻，对GR具有高度特异性。此外，B53能够通过口服药物干预显着缓解小鼠模型的皮炎。
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