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 14h exhibited IC₅₀ of 0.57 nM for PDE4D and >4100-fold selectivity over other PDE families. Compound 14h inhibited release of inflammatory cytokines of TNF-α (IC₅₀ = 34.2 μM) and IL-6 (IC₅₀ = 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, 14h 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 14h is a strong candidate for the topical treatment of psoriasis.

中文翻译：

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用于银屑病局部治疗的新型选择性 PDE4 抑制剂的设计、合成和生物学评价


银屑病是一种复杂的慢性炎症性疾病。目前的药物有助于控制银屑病的症状，但无法治愈，这促使人们发现新药。我们在本文中报告了用于治疗银屑病的新型磷酸二酯酶 4 （PDE4） 抑制剂的发现。我们设计合成了 45 种新化合物，其中 14 h 对 PDE4D 的 IC₅₀ 为 0.57 nM，选择性是其他 PDE 家族的 >4100 倍。化合物 14h 抑制 Raw264.7 细胞中 TNF-α （IC₅₀ = 34.2 μM） 和 IL-6 （IC₅₀ = 40.9 μM） 炎性细胞因子的释放，并降低银屑病小鼠皮肤中 IL-1β 和 IL-17A 的表达。此外，14 h 减轻了小鼠模型中 IMQ 诱导的银屑病，并降低了小鼠背部皮肤的红斑水平、鳞屑和厚度。简而言之，我们的结果表明 PDE4 抑制剂 14h 是局部治疗银屑病的有力候选者。