Song Zhendong, Huang Yi-You, Hou Ke-Qiang, Liu Lu, Zhou Feng, Huang Yue, Wan Guohui, Luo Hai-Bin, Xiong Xiao-Feng
National-Local Joint Engineering Laboratory of Druggability and New Drugs Evaluation, Guangdong Province Engineering Laboratory for Druggability and New Drug Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, 510006 Guangzhou, P. R. China.
Key Laboratory of Tropical Biological Resources of Ministry of Education, School of Pharmaceutical Sciences, Hainan University, 570228 Haikou, P. R. China.
J Med Chem. 2022 Mar 10;65(5):4238-4254. doi: 10.1021/acs.jmedchem.1c02058. Epub 2022 Feb 21.
Psoriasis is a common immune-mediated skin disorder manifesting in abnormal skin plaques, and phosphodiesterase 4 (PDE4) is an effective target for the treatment of inflammatory diseases such as psoriasis. Toddacoumalone is a natural PDE4 inhibitor with moderate potency and imperfect drug-like properties. To discover novel and potent PDE4 inhibitors with considerable druggability, a series of toddacoumalone derivatives were designed and synthesized, leading to the compound (2,4)-6-ethyl-2-(2-hydroxyethyl)-2,8-dimethyl-4-(2-methylprop-1-en-1-yl)-2,3,4,6-tetrahydro-5-pyrano[3,2-][1,8]naphthyridin-5-one () with high inhibitory potency (IC = 3.1 nM), satisfactory selectivity, favorable skin permeability, and a well-characterized binding mechanism. Encouragingly, topical administration of exhibited remarkable therapeutic effects in an imiquimod-induced psoriasis mouse model.
银屑病是一种常见的免疫介导性皮肤病，表现为异常的皮肤斑块，磷酸二酯酶4（PDE4）是治疗银屑病等炎症性疾病的有效靶点。滨蒿内酯是一种天然的PDE4抑制剂，活性中等，类药性质欠佳。为了发现新型、强效且具有良好成药性的PDE4抑制剂，设计并合成了一系列滨蒿内酯衍生物，得到了化合物（2,4）-6-乙基-2-（2-羟乙基）-2,8-二甲基-4-（2-甲基丙-1-烯-1-基）-2,3,4,6-四氢-5-吡喃并[3,2-][1,8]萘啶-5-酮（），其具有高抑制活性（IC = 3.1 nM）、令人满意的选择性、良好的皮肤渗透性以及明确的结合机制。令人鼓舞的是，在咪喹莫特诱导的银屑病小鼠模型中，局部应用该化合物显示出显著的治疗效果。
