Design, synthesis and biological evaluation of novel AhR agonists

VernacularTitle:新型AhR激动剂的设计、合成及活性研究
Author: Jian-min JIA ; Ya-xian CAI ; Zi-xing HAN ; Jia-jia XU ; Kai-ming CAI ; Xiao-hui HU
Publication Type:Research Article
Keywords: aryl hydrocarbon receptor; agonist; Tapinarof; IFN-γ; photochemical stability
From: Acta Pharmaceutica Sinica 2024;59(11):2997-3005
CountryChina
Language:Chinese
Abstract: The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that regulates gene expression in a range of cells, including immune and epithelial cells. AhR signaling plays important roles in the immune system in both health and disease states. Tapinarof is a first-in-class small-molecule topical therapeutic AhR modulating agent launched for the treatment of psoriasis. To improve the activity and chemical stability of Tapinarof, a series of 2-phenylchromen-4-one derivatives were designed, synthesized and evaluated as novel AhR agonists. Compounds 5a, 5c, 5e and 5f potently activated AhR with an EC₅₀ value of 7, 9, 6 and 6 nmol·L^-1, respectively, which are 10-14 fold more potent than Tapinarof. Compounds 5a and 5e exhibit comparable inhibitory effects on IFN-γ production as Tapinarof. Furthermore, compounds 5a-5f exhibited favorable photochemical stability compared to Tapinarof. The compounds may eventually serve as lead compounds for the development of new AhR agonists.