Details

Autor(en) / Beteiligte

• Pang, Jin-Ping
• Hu, Xue-Ping
• Wang, Yun-Xia
• Liao, Jia-Ning
• Chai, Xin
• Wang, Xu-Wen
• Shen, Chao
• Wang, Jia-Jia
• Zhang, Lu-Lu
• Wang, Xin-Yue
• Zhu, Feng
• Weng, Qin-Jie
• Xu, Lei
• Hou, Ting-Jun
• Li, Dan

Titel

Discovery of a novel nonsteroidal selective glucocorticoid receptor modulator by virtual screening and bioassays

Ist Teil von

• Acta pharmacologica Sinica, 2022-09, Vol.43 (9), p.2429-2438

Ort / Verlag

United States: Nature Publishing Group

Erscheinungsjahr

2022

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• Synthetic glucocorticoids (GCs) have been widely used in the treatment of a broad range of inflammatory diseases, but their clinic use is limited by undesired side effects such as metabolic disorders, osteoporosis, skin and muscle atrophies, mood disorders and hypothalamic-pituitary-adrenal (HPA) axis suppression. Selective glucocorticoid receptor modulators (SGRMs) are expected to have promising anti-inflammatory efficacy but with fewer side effects caused by GCs. Here, we reported HT-15, a prospective SGRM discovered by structure-based virtual screening (VS) and bioassays. HT-15 can selectively act on the NF-κB/AP1-mediated transrepression function of glucocorticoid receptor (GR) and repress the expression of pro-inflammation cytokines (i.e., IL-1β, IL-6, COX-2, and CCL-2) as effectively as dexamethasone (Dex). Compared with Dex, HT-15 shows less transactivation potency that is associated with the main adverse effects of synthetic GCs, and no cross activities with other nuclear receptors. Furthermore, HT-15 exhibits very weak inhibition on the ratio of OPG/RANKL. Therefore, it may reduce the side effects induced by normal GCs. The bioactive compound HT-15 can serve as a starting point for the development of novel therapeutics for high dose or long-term anti-inflammatory treatment.