Identification of Dihydrobenzofuran Neolignans as Novel PDE4 Inhibitors and Evaluation of Antiatopic Dermatitis Efficacy in DNCB-Induced Mice Model

  • J Med Chem. 2024 Mar 28;67(6):4855-4869. doi: 10.1021/acs.jmedchem.3c02424.
Chenming Gu  1 ,  Jiayuan Liu  2 ,  Fei Qian  3 ,  Wenchao Yu  1 ,  Doudou Huang  1 ,  Jingshan Shen  2 ,  Chenguo Feng  4 ,  Kaixian Chen  1 ,  Yiming Li  1 ,  Xiangrui Jiang  2 ,  Yechun Xu  2  5  6 ,  Liuqiang Zhang  1
Affiliations
  • 1. School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
  • 2. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 3. Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
  • 4. The Research Center of Chiral Drugs, Innovation Research Institute of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
  • 5. University of Chinese Academy of Sciences, Beijing 100049, China.
  • 6. School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China.
PMID: 38489246 DOI: 10.1021/acs.jmedchem.3c02424
Abstract

Atopic dermatitis is a chronic relapsing skin disease characterized by recurrent, pruritic, localized eczema, while PDE4 inhibitors have been reported to be effective as antiatopic dermatitis agents. 3',4-O-dimethylcedrusin (DCN) is a natural dihydrobenzofuran neolignan isolated from Magnolia biondii with moderate potency against PDE4 (IC50 = 3.26 ± 0.28 μM) and a binding mode similar to that of apremilast, an approved PDE4 Inhibitor for the treatment of psoriasis. The structure-based optimization of DCN led to the identification of 7b-1 that showed high inhibitory potency on PDE4 (IC50 = 0.17 ± 0.02 μM), good anti-TNF-α activity (EC50 = 0.19 ± 0.10 μM), remarkable selectivity profile, and good skin permeability. The topical treatment of 7b-1 resulted in the significant benefits of pharmacological intervention in a DNCB-induced atopic dermatitis-like mice model, demonstrating its potential for the development of novel antiatopic dermatitis agents.

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