{"title":"Structure-Based Optimization of Moracin M as Potent and Selective PDE4 Inhibitors with Antipsoriasis Effects","authors":"Furong Zhang, Tiansheng Zheng, Xue Wang, Yu Chen, Feng Zhang, Xingfu Liu, Sen Wang, Guofeng Yang, Shenghong Xie, Qi Wu, Chao Xu, Qian Zhou, Deyan Wu*, Hai-Bin Luo* and Yi-You Huang*, ","doi":"10.1021/acs.jmedchem.5c0026610.1021/acs.jmedchem.5c00266","DOIUrl":null,"url":null,"abstract":"<p >Psoriasis is a complex chronic inflammatory disease that severely affects the quality of life of patients. However, current medications could only control the symptoms but not cure psoriasis with unmet medical needs. Herein, structure-based optimizations of natural product moracin M (IC<sub>50</sub> of 2.9 μM) led to a novel PDE4 inhibitor <b>L30</b> with greatly improved potency (IC<sub>50</sub> of 8.6 nM) and remarkable selectivity across other PDEs families (>201-fold). The binding pattern of <b>L30</b> with PDE4 revealed by cocrystal structure was different from that of roflumilast. Besides, <b>L30</b> could effectively inhibit the release of inflammatory cytokines and chemokines in Raw264.7 and HaCaT cell lines. Furthermore, topical administration of <b>L30</b> exhibited significant therapeutic effects in an imiquimod-induced psoriasis mouse model. These findings highlighted the potential of PDE4 inhibitor <b>L30</b> as a novel lead for the treatment of psoriasis.</p>","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"68 6","pages":"6789–6803 6789–6803"},"PeriodicalIF":6.8000,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Medicinal Chemistry","FirstCategoryId":"3","ListUrlMain":"https://pubs.acs.org/doi/10.1021/acs.jmedchem.5c00266","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
引用次数: 0
Abstract
Psoriasis is a complex chronic inflammatory disease that severely affects the quality of life of patients. However, current medications could only control the symptoms but not cure psoriasis with unmet medical needs. Herein, structure-based optimizations of natural product moracin M (IC50 of 2.9 μM) led to a novel PDE4 inhibitor L30 with greatly improved potency (IC50 of 8.6 nM) and remarkable selectivity across other PDEs families (>201-fold). The binding pattern of L30 with PDE4 revealed by cocrystal structure was different from that of roflumilast. Besides, L30 could effectively inhibit the release of inflammatory cytokines and chemokines in Raw264.7 and HaCaT cell lines. Furthermore, topical administration of L30 exhibited significant therapeutic effects in an imiquimod-induced psoriasis mouse model. These findings highlighted the potential of PDE4 inhibitor L30 as a novel lead for the treatment of psoriasis.
期刊介绍：
The Journal of Medicinal Chemistry is a prestigious biweekly peer-reviewed publication that focuses on the multifaceted field of medicinal chemistry. Since its inception in 1959 as the Journal of Medicinal and Pharmaceutical Chemistry, it has evolved to become a cornerstone in the dissemination of research findings related to the design, synthesis, and development of therapeutic agents.
The Journal of Medicinal Chemistry is recognized for its significant impact in the scientific community, as evidenced by its 2022 impact factor of 7.3. This metric reflects the journal's influence and the importance of its content in shaping the future of drug discovery and development. The journal serves as a vital resource for chemists, pharmacologists, and other researchers interested in the molecular mechanisms of drug action and the optimization of therapeutic compounds.
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