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

Abstract

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.

• Authors: Zhendong Song, Yi-You Huang, Ke-Qiang Hou, Lu Liu, Feng Zhou, Yue Huang, Guohui Wan, Hai-Bin Luo, Xiao-Feng Xiong
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 65 Issue 5 Pg. 4238-4254 (03 10 2022) ISSN: 1520-4804 [Electronic] United States
• PMID: 35188767 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Phosphodiesterase 4 Inhibitors
• Cyclic Nucleotide Phosphodiesterases, Type 4

Topics

• Administration, Topical
• Animals
• Cyclic Nucleotide Phosphodiesterases, Type 4 (metabolism)
• Mice
• Phosphodiesterase 4 Inhibitors (pharmacology, therapeutic use)
• Psoriasis (chemically induced, drug therapy)
• Skin