School of Pharmacy and Food Engineering, Wuyi University, Jiangmen 529020, China.
Guangdong Key Laboratory of Animal Conservation and Resource Utilization, Guangdong Public Laboratory of Wild Animal Conservation and Utilization, Institute of Zoology, Guangdong Academy of Sciences, Guangzhou, Guangdong 510260, China.
J Med Chem. 2024 Nov 28;67(22):20353-20371. doi: 10.1021/acs.jmedchem.4c01804. Epub 2024 Nov 13.
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.
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，但不能治愈，因此需要发现新的药物。我们在本文中报告了新型磷酸二酯酶 4（PDE4）抑制剂的发现，用于治疗银屑病。我们设计并合成了 45 种新化合物，其中化合物 对 PDE4D 的 IC 为 0.57 nM，对其他 PDE 家族具有 >4100 倍的选择性。化合物 在 Raw264.7 细胞中抑制 TNF-α（IC = 34.2 μM）和 IL-6（IC = 40.9 μM）的炎症细胞因子释放，并降低银屑病小鼠皮肤中 IL-1β和 IL-17A 的表达。此外， 减轻了咪喹莫特诱导的小鼠银屑病模型中的红斑程度、鳞屑和背部皮肤厚度。总之，我们的结果表明，PDE4 抑制剂 是治疗银屑病的局部治疗的有力候选药物。
