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

Abstract

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.

• Authors: Jin-Ping Pang, Xue-Ping Hu, Yun-Xia Wang, Jia-Ning Liao, Xin Chai, Xu-Wen Wang, Chao Shen, Jia-Jia Wang, Lu-Lu Zhang, Xin-Yue Wang, Feng Zhu, Qin-Jie Weng, Lei Xu, Ting-Jun Hou, Dan Li
• Journal: Acta pharmacologica Sinica (Acta Pharmacol Sin) Vol. 43 Issue 9 Pg. 2429-2438 (Sep 2022) ISSN: 1745-7254 [Electronic] United States
• PMID: 35110698 (Publication Type: Journal Article)
• Copyright: © 2022. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.

Chemical References

• Anti-Inflammatory Agents
• Glucocorticoids
• Receptors, Glucocorticoid

Topics

• Anti-Inflammatory Agents (pharmacology)
• Biological Assay
• Glucocorticoids (pharmacology)
• Prospective Studies
• Receptors, Glucocorticoid (metabolism)