2. Academic Validation
  3. Development of selective heterocyclic PDE4 inhibitors for treatment of psoriasis

Development of selective heterocyclic PDE4 inhibitors for treatment of psoriasis

  • Eur J Med Chem. 2024 Oct 8:280:116930. doi: 10.1016/j.ejmech.2024.116930.
Gang Li 1,  Dengqin He 2,  Xudong Qian 2,  Yuanhui Liu 1,  Yanghui Ou 1,  Mengjie Li 1,  Liyan Song 1,  Zichen Xu 3,  Guoping Zhang 1,  Jun Wang 2,  Wei Pan 2,  Jiaxin Chen 1,  Yali Zhang 1,  Jia-Qiang Wu 4,  Dandan Chen 2,  Cheng Chen 1,  Siying Peng 2,  Hongliang Yao 5,  Hengming Ke 6
Affiliations

Affiliations

  • 1 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.
  • 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; School of Pharmacy and Food Engineering, Wuyi University, Jiangmen, 529020, China.
  • 3 Institute for Advanced and Applied Chemical Synthesis, Jinan University, Guangzhou, 510632, China.
  • 4 School of Pharmacy and Food Engineering, Wuyi University, Jiangmen, 529020, China.
  • 5 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. Electronic address: yaohl@giz.gd.cn.
  • 6 Department of Biochemistry and Biophysics, The University of North Carolina, 120 Mason Farm Road, Chapel Hill, NC, 27599, USA. Electronic address: hke@med.unc.edu.
PMID: 39383652 DOI: 10.1016/j.ejmech.2024.116930
Abstract

Psoriasis is a chronic autoimmune disease that badly affects the life quality of patients and their families. Inadequate efficacy, safety risks, high cost and low compliance of current psoriasis drugs urge development of novel small molecular drugs. In this study, two series of 37 novel compounds were designed and synthesized as inhibitors of phosphodiesterase 4 (PDE4) that specifically hydrolyzes second messenger cAMP and is an effective target for treatment of inflammatory diseases. Comprehensive structural-activity optimization led to finding of inhibitor 2e with IC50 = 2.4 nM for PDE4D and >4100-fold selectivity over other PDE families. Compound 2e inhibited the release of TNF-α (IC50 = 21.36 μM) and IL-6 (IC50 = 29.22 μM) in the LPS-stimulated Raw264.7 cells. Topical application of 2e exhibited remarkable therapeutic efficacy in imiquimod-induced psoriasis mice model, suggesting that 2e is a strong drug candidate for treatment of psoriasis.

Keywords

Anti-inflammation; PDE4 inhibitor; Psoriasis.

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