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

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.