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<i>R</i>,4<i>S</i>)-6-ethyl-2-(2-hydroxyethyl)-2,8-dimethyl-4-(2-methylprop-1-en-1-yl)-2,3,4,6-tetrahydro-5<i>H</i>-pyrano[3,2-<i>c</i>][1,8]naphthyridin-5-one (<b>33a</b>) with high inhibitory potency (IC<sub>50</sub> = 3.1 nM), satisfactory selectivity, favorable skin permeability, and a well-characterized binding mechanism. Encouragingly, topical administration of <b>33a</b> exhibited remarkable therapeutic effects in an imiquimod-induced psoriasis mouse model.