Design, Synthesis, and Biological Evaluation of New Selective PDE4 Inhibitors for Topical Treatment of Psoriasis
Psoriasis is a complex and chronic inflammatory disease. Current drugs help control the symptoms of psoriasis but make no cure, urging discovery of novel drugs. We report in this paper the discovery of new phosphodiesterase 4 (PDE4) inhibitors for treatment of psoriasis. We designed and synthesized 45 new compounds, among which <b>14h</b> exhibited IC<sub>50</sub> of 0.57 nM for PDE4D and >4100-fold selectivity over other PDE families. Compound <b>14h</b> inhibited release of inflammatory cytokines of TNF-α (IC<sub>50</sub> = 34.2 μM) and IL-6 (IC<sub>50</sub> = 40.9 μM) in Raw264.7 cells and reduced the expression of IL-1β and IL-17A in the skin of psoriasis mice. In addition, <b>14h</b> alleviated IMQ-induced psoriasis in the mouse model and reduced the erythema level, scales, and thickness of the back skin of the mice. In short, our results suggested that PDE4 inhibitor <b>14h</b> is a strong candidate for the topical treatment of psoriasis.
Authors
- Hengming Ke
- Wei Pan
- Yanghui Ou
- Dengqin He
- Jia‐Qiang Wu (ORCID: https://orcid.org/0000-0001-5067-7616)
- Xudong Qian (ORCID: https://orcid.org/0000-0002-6183-256X)
- Jiaxin Chen (ORCID: https://orcid.org/0000-0003-1506-2223)
- Dandan Chen (ORCID: https://orcid.org/0000-0003-0918-7337)
- Liu Y (ORCID: https://orcid.org/0000-0001-8568-623X)
- Mengjie Li (ORCID: https://orcid.org/0000-0001-8573-7025)
- Guoping Zhang (ORCID: https://orcid.org/0000-0003-2207-7669)
- Zichen Xu (ORCID: https://orcid.org/0000-0002-6469-7869)
- Hongliang Yao (ORCID: https://orcid.org/0000-0002-2900-3251)
- Yan Geng (ORCID: https://orcid.org/0009-0008-2658-7598)
- Jun Wang (ORCID: https://orcid.org/0000-0001-8183-7600)
- Gang Li (ORCID: https://orcid.org/0000-0003-4191-7643)
Institutions
- University of North Carolina at Chapel Hill (US)
- Jinan University (CN)
- Guangdong Academy of Sciences (CN)
- Institute of Zoology (CN)
- Wuyi University (CN)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2024-11-13
- DOI
- https://doi.org/10.1021/acs.jmedchem.4c01804
- Citations
- 5
- Primary Topic
- Psoriasis: Treatment and Pathogenesis
- Type
- article
- Field-Weighted Citation Impact
- 1.20
Funders
- Guangdong Academy of Sciences
- Special Project for Research and Development in Key areas of Guangdong Province
- Basic and Applied Basic Research Foundation of Guangdong Province