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  3. Design, Synthesis, and Biological Evaluation of New Selective PDE4 Inhibitors for Topical Treatment of Psoriasis

Design, Synthesis, and Biological Evaluation of New Selective PDE4 Inhibitors for Topical Treatment of Psoriasis

  • J Med Chem. 2024 Nov 28;67(22):20353-20371. doi: 10.1021/acs.jmedchem.4c01804.
Dengqin He 1 2,  Gang Li 2,  Jia-Qiang Wu 1,  Yan Geng 2,  Xudong Qian 1 2,  Yuanhui Liu 2,  Yanghui Ou 2,  Mengjie Li 2,  Jun Wang 1 2,  Wei Pan 1 2,  Guoping Zhang 2,  Dandan Chen 1 2,  Jiaxin Chen 2,  Zichen Xu 3,  Hengming Ke 4,  Hongliang Yao 2
Affiliations

Affiliations

  • 1 School of Pharmacy and Food Engineering, Wuyi University, Jiangmen 529020, China.
  • 2 Guangdong Key Laboratory of Animal Conservation and Resource Utilization, Guangdong Public Laboratory of Wild Animal Conservation and Utilization, Institute of Zoology, Guangdong Academy of Sciences, Guangzhou, Guangdong 510260, China.
  • 3 Institute for Advanced and Applied Chemical Synthesis, Jinan University, Guangzhou 510632, China.
  • 4 Department of Biochemistry and Biophysics, The University of North Carolina, 120 Mason Farm Road, Chapel Hill, North Carolina 27599, United States.
PMID: 39535061 DOI: 10.1021/acs.jmedchem.4c01804
Abstract

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 14h exhibited IC50 of 0.57 nM for PDE4D and >4100-fold selectivity over Other PDE families. Compound 14h inhibited release of inflammatory cytokines of TNF-α (IC50 = 34.2 μM) and IL-6 (IC50 = 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, 14h 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 14h is a strong candidate for the topical treatment of psoriasis.

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