Development of selective heterocyclic PDE4 inhibitors for treatment of psoriasis.

Psoriasis is a chronic autoimmune disease that badly affects the life quality of patients and their families. Inadequate efficacy, safety risks, high cost and low compliance of current psoriasis drugs urge development of novel small molecular drugs. In this study, two series of 37 novel compounds were designed and synthesized as inhibitors of phosphodiesterase 4 (PDE4) that specifically hydrolyzes second messenger cAMP and is an effective target for treatment of inflammatory diseases. Comprehensive structural-activity optimization led to finding of inhibitor 2e with IC = 2.4 nM for PDE4D and >4100-fold selectivity over other PDE families. Compound 2e inhibited the release of TNF-α (IC = 21.36 μM) and IL-6 (IC = 29.22 μM) in the LPS-stimulated Raw264.7 cells. Topical application of 2e exhibited remarkable therapeutic efficacy in imiquimod-induced psoriasis mice model, suggesting that 2e is a strong drug candidate for treatment of psoriasis.