Design, Optimization, and Biological Evaluation of Novel Tapinarof Analogues as AHR Agonists for Topical Psoriasis Treatment

Psoriasis is a chronic inflammatory disease that affects the quality of life of patients. The aromatic hydrocarbon receptor (AHR) plays a pivotal role in maintaining the skin barrier integrity. In this study, we conducted a comprehensive analysis of the structure-activity relationship of Tapinarof analogues. Among them, <b>B19</b> showed low cytotoxicity (>40 μM) and potent AHR agonist activity with an EC₅₀ value of 2.01 nM, which was 14-fold stronger than that of Tapinarof (28.93 nM). <b>B19</b> exhibited the ability to elevate the transcript levels of key AHR downstream pathway target genes, including CYP1A1 and CYP1B1. Upon topical application, <b>B19</b> significantly ameliorated imiquimod (IMQ)-induced psoriasis-like cutaneous manifestations and repaired the barrier function of skin, concurrently downregulating the expression levels of CD206, CD36, IL-18, and MCP-1. These findings suggested that <b>B19</b> represents a potential alternative to Tapinarof for the topical psoriasis treatment.