转换抑制
交易激励
化学
糖皮质激素受体
糖皮质激素
磺胺
IC50型
药理学
受体
立体化学
生物化学
体外
内科学
基因表达
医学
基因
作者
Dan Li,Qinqin Xia,Jinping Pang,Xueping Hu,Longling Wang,Jiajia Wang,Zhaoxu Yang,Lei Xu,Siyu Wang,Qinjie Weng,Sunliang Cui,Tingjun Hou
标识
DOI:10.1021/acs.jmedchem.2c01082
摘要
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.
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