Discovery and Structural Optimization of Toddacoumalone Derivatives as Novel PDE4 Inhibitors for the Topical Treatment of Psoriasis,Journal of Medicinal Chemistry

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Discovery and Structural Optimization of Toddacoumalone Derivatives as Novel PDE4 Inhibitors for the Topical Treatment of Psoriasis
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2022-02-21 , DOI: 10.1021/acs.jmedchem.1c02058
Zhendong Song ₁ , Yi-You Huang _{1,

2} , Ke-Qiang Hou ₁ , Lu Liu ₁ , Feng Zhou ₁ , Yue Huang ₁ , Guohui Wan ₁ , Hai-Bin Luo _{1,

2} , Xiao-Feng Xiong ₁

Affiliation

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 (2R,4S)-6-ethyl-2-(2-hydroxyethyl)-2,8-dimethyl-4-(2-methylprop-1-en-1-yl)-2,3,4,6-tetrahydro-5H-pyrano[3,2-c][1,8]naphthyridin-5-one (33a) with high inhibitory potency (IC₅₀ = 3.1 nM), satisfactory selectivity, favorable skin permeability, and a well-characterized binding mechanism. Encouragingly, topical administration of 33a exhibited remarkable therapeutic effects in an imiquimod-induced psoriasis mouse model.

中文翻译：

托达香豆酮衍生物作为用于银屑病局部治疗的新型 PDE4 抑制剂的发现和结构优化

银屑病是一种常见的免疫介导的皮肤病，表现为皮肤异常斑块，而磷酸二酯酶 4（PDE4）是治疗银屑病等炎症性疾病的有效靶点。Toddacoumalone 是一种天然 PDE4 抑制剂，具有中等效力和不完善的药物样特性。为了发现具有相当成药性的新型强效 PDE4 抑制剂，设计并合成了一系列托达香豆酮衍生物，得到化合物 (2 R ,4 S )-6-ethyl-2-(2-hydroxyethyl)-2,8-dimethyl -4-(2-methylprop-1-en-1-yl)-2,3,4,6-tetrahydro-5 H -pyrano[3,2 - c ][1,8]naphthyridin-5-one ( 33a ) 具有高抑制效力 (IC ₅₀= 3.1 nM)、令人满意的选择性、良好的皮肤渗透性和良好表征的结合机制。令人鼓舞的是， 33a的局部给药在咪喹莫特诱导的银屑病小鼠模型中表现出显着的治疗效果。

更新日期：2022-02-21

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