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.
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; School of Pharmacy and Food Engineering, Wuyi University, Jiangmen, 529020, China.
Eur J Med Chem. 2024 Dec 15;280:116930. doi: 10.1016/j.ejmech.2024.116930. Epub 2024 Oct 9.
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.
银屑病是一种慢性自身免疫性疾病，严重影响患者及其家属的生活质量。目前银屑病药物疗效不足、存在安全风险、费用高、患者顺应性低，因此需要开发新型小分子药物。本研究设计并合成了两系列 37 种新型化合物，作为磷酸二酯酶 4（PDE4）抑制剂，PDE4 特异性水解第二信使 cAMP，是治疗炎症性疾病的有效靶点。通过综合结构-活性优化，发现 PDE4D 的抑制剂 2e，其 IC50 为 2.4 nM，对其他 PDE 家族具有 >4100 倍的选择性。化合物 2e 抑制 LPS 刺激的 Raw264.7 细胞中 TNF-α（IC50=21.36 μM）和 IL-6（IC50=29.22 μM）的释放。2e 在咪喹莫特诱导的银屑病小鼠模型中的局部应用表现出显著的治疗效果，表明 2e 是治疗银屑病的有效药物候选物。
