Identification of triazolopyridine derivatives as a new class of AhR agonists and evaluation of anti-psoriasis effect in a mouse model

The Aryl Hydrocarbon Receptor (AhR), a ligand-dependent transcription factor, can regulate the immune balance of Th17/22 and Treg cells, which plays an important role in the development and maintenance of the skin barrier. We herein report the discovery of triazolopyridine derivatives as a new class of AhR agonists. Structure-activity relationship analyses led to the identification of the most active compound, 6-bromo-2-(4-bromophenyl)-[1,2,4]triazolo[1,5-a]pyridine (12a), with an EC₅₀ (50% effective concentration) value of 0.03 nM. Compound 12a could induce rapid nuclear enrichment of AhR, trigger the transcription of downstream genes and promote skin barrier repair. Topical or oral administration of 12a could significantly alleviate imiquimod (IMQ)-induced psoriasis-like skin lesion. Considering the excellent in vivo anti-psoriasis activity as well as good pharmacokinetic properties, 12a could be a promising lead compound for drug discovery against psoriasis, and deserving further investigation.