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

  • J Med Chem. 2022 Mar 10;65(5):4238-4254. 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
Affiliations
  • 1. 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.
  • 2. Key Laboratory of Tropical Biological Resources of Ministry of Education, School of Pharmaceutical Sciences, Hainan University, 570228 Haikou, P. R. China.
PMID: 35188767 DOI: 10.1021/acs.jmedchem.1c02058
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.

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