Psoriasis is a complex and chronic inflammatory disease. Current drugs help control the symptoms of psoriasis but make no cure, urging discovery of novel drugs. We report in this paper the discovery of new phosphodiesterase 4 (PDE4) inhibitors for treatment of psoriasis. We designed and synthesized 45 new compounds, among which exhibited IC of 0.57 nM for PDE4D and >4100-fold selectivity over other PDE families. Compound inhibited release of inflammatory cytokines of TNF-α (IC = 34.2 μM) and IL-6 (IC = 40.9 μM) in Raw264.7 cells and reduced the expression of IL-1β and IL-17A in the skin of psoriasis mice. In addition, alleviated IMQ-induced psoriasis in the mouse model and reduced the erythema level, scales, and thickness of the back skin of the mice. In short, our results suggested that PDE4 inhibitor is a strong candidate for the topical treatment of psoriasis.
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http://dx.doi.org/10.1021/acs.jmedchem.4c01804 | DOI Listing |
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