Psoriasis is a complex chronic inflammatory disease that severely affects the quality of life of patients. However, current medications could only control the symptoms but not cure psoriasis with unmet medical needs. Herein, structure-based optimizations of natural product moracin M (IC of 2.9 μM) led to a novel PDE4 inhibitor with greatly improved potency (IC of 8.6 nM) and remarkable selectivity across other PDEs families (>201-fold). The binding pattern of with PDE4 revealed by cocrystal structure was different from that of roflumilast. Besides, could effectively inhibit the release of inflammatory cytokines and chemokines in Raw264.7 and HaCaT cell lines. Furthermore, topical administration of exhibited significant therapeutic effects in an imiquimod-induced psoriasis mouse model. These findings highlighted the potential of PDE4 inhibitor as a novel lead for the treatment of psoriasis.
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