Structure-Based Optimization of Moracin M as Potent and Selective PDE4 Inhibitors with Antipsoriasis Effects

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 (IC₅₀ of 2.9 μM) led to a novel PDE4 inhibitor L30 with greatly improved potency (IC₅₀ of 8.6 nM) and remarkable selectivity across other PDEs families (>201-fold). The binding pattern of L30 with PDE4 revealed by cocrystal structure was different from that of roflumilast. Besides, L30 could effectively inhibit the release of inflammatory cytokines and chemokines in Raw264.7 and HaCaT cell lines. Furthermore, topical administration of L30 exhibited significant therapeutic effects in an imiquimod-induced psoriasis mouse model. These findings highlighted the potential of PDE4 inhibitor L30 as a novel lead for the treatment of psoriasis.