Structural modification of imperatorin affords promising dual AhR/PDE4 modulators for anti-inflammatory therapy

Precise and effective control of inflammation is critical for treating inflammatory diseases, highlighting an urgent clinical demand for improved anti-inflammatory agents. The aryl hydrocarbon receptor (AhR) is a key nuclear transcription factor in immune regulation, but clinically relevant AhR agonists such as Tapinarof show limited efficacyas monotherapy for psoriasis, resulting in frequent combination with PDE4 inhibitors in clinical practice to achieve optimal therapeutic outcomes because of the extensive crosstalk between AhR and PDE4 in inflammation. Our research group previously found that Imperatorin (Imp) is a natural AhR agonist with anti-inflammatory activity in vivo; however, its AhR agonist potency is far inferior to clinical candidates. Our research group previously found that Imperatorin is a natural AhR agonist with anti-inflammatory activity in vivo. Herein, we designed and synthesized a series of Imp derivatives to enhance AhR agonistic activity. The optimal compound T29 exhibited an EC₅₀ of 0.11 μM in the HepG2-Lucia™ AhR assay. Moreover, T29 acted as a dual AhR/PDE4 modulator via the AhR-CYP1A1 and cAMP-PKA-CREB signaling pathways. In the imiquimod-induced psoriasis-like mouse model, T29 effectively alleviated epidermal hyperplasia and inflammatory infiltration and strongly inhibited IL-17A/F via topical administration. These findings identify T29 as a promising active dual-targeting anti-inflammatory agent worthy of further development.