TY - JOUR AU - Pang Jin-ping AU - Hu Xue-ping AU - Wang Yun-xia AU - Liao Jia-ning AU - Chai Xin AU - Wang Xu-wen AU - Shen Chao AU - Wang Jia-jia AU - Zhang Lu-lu AU - Wang Xin-yue AU - Zhu Feng AU - Weng Qin-jie AU - Xu Lei AU - Hou Ting-jun AU - Li Dan PY - 2022 TI - Discovery of a novel nonsteroidal selective glucocorticoid receptor modulator by virtual screening and bioassays JF - Acta Pharmacologica Sinica; Vol 43, No 9 (September 2022): Acta Pharmacologica Sinica Y2 - 2022 KW - N2 - 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. UR - http://www.chinaphar.com/article/view/10673