2. Academic Validation
  3. Identification of Dihydrobenzofuran Neolignans as Novel PDE4 Inhibitors and Evaluation of Antiatopic Dermatitis Efficacy in DNCB-Induced Mice Model

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

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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