Design, Synthesis, and Biological Evaluation of New Selective PDE4 Inhibitors for Topical Treatment of Psoriasis

IF 6.8 1区医学 Q1 CHEMISTRY, MEDICINAL Journal of Medicinal Chemistry Pub Date : 2024-11-13 DOI:10.1021/acs.jmedchem.4c01804

Dengqin He, Gang Li, Jia-Qiang Wu, Yan Geng, Xudong Qian, Yuanhui Liu, Yanghui Ou, Mengjie Li, Jun Wang, Wei Pan, Guoping Zhang, Dandan Chen, Jiaxin Chen, Zichen Xu, Hengming Ke, Hongliang Yao

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Abstract

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.

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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

牛皮癣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，但无法根治，因此需要发现新的药物。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。我们设计并合成了 45 个新化合物，其中 14h 对 PDE4D 的 IC50 值为 0.57 nM，与其他 PDE 家族相比具有 4100 倍的选择性。化合物 14h 能抑制 Raw264.7 细胞中 TNF-α （IC50 = 34.2 μM）和 IL-6 （IC50 = 40.9 μM）等炎症细胞因子的释放，并能降低银屑病小鼠皮肤中 IL-1β 和 IL-17A 的表达。此外，14 小时还能缓解 IMQ 诱导的银屑病小鼠模型，并减少小鼠背部皮肤的红斑程度、鳞屑和厚度。总之，我们的研究结果表明，PDE4 抑制剂 14h 是局部治疗银屑病的有力候选药物。

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来源期刊

Journal of Medicinal Chemistry 医学-医药化学

CiteScore

4.00

自引率

11.00%

发文量

804

审稿时长

1.9 months

期刊介绍： The Journal of Medicinal Chemistry is a prestigious biweekly peer-reviewed publication that focuses on the multifaceted field of medicinal chemistry. Since its inception in 1959 as the Journal of Medicinal and Pharmaceutical Chemistry, it has evolved to become a cornerstone in the dissemination of research findings related to the design, synthesis, and development of therapeutic agents. The Journal of Medicinal Chemistry is recognized for its significant impact in the scientific community, as evidenced by its 2022 impact factor of 7.3. This metric reflects the journal's influence and the importance of its content in shaping the future of drug discovery and development. The journal serves as a vital resource for chemists, pharmacologists, and other researchers interested in the molecular mechanisms of drug action and the optimization of therapeutic compounds.