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, B19 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). B19 exhibited the ability to elevate the transcript levels of key AHR downstream pathway target genes, including CYP1A1 and CYP1B1. Upon topical application, B19 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 B19 represents a potential alternative to Tapinarof for the topical psoriasis treatment.