Development of selective heterocyclic PDE4 inhibitors for treatment of psoriasis

Gang Li; Dengqin He; Xudong Qian; Yuanhui Liu; Yanghui Ou; Mengjie Li; Liyan Song; Zichen Xu; Guoping Zhang; Jun Wang; Wei Pan; Jiaxin Chen; Yali Zhang; Jia-Qiang Wu; Dandan Chen; Cheng Chen; Siying Peng; Hongliang Yao; Hengming Ke

doi:10.1016/j.ejmech.2024.116930

Development of selective heterocyclic PDE4 inhibitors for treatment of psoriasis

Eur J Med Chem. 2024 Dec 15:280:116930. doi: 10.1016/j.ejmech.2024.116930. Epub 2024 Oct 9.

Authors

Gang Li¹, Dengqin He², Xudong Qian², Yuanhui Liu¹, Yanghui Ou¹, Mengjie Li¹, Liyan Song¹, Zichen Xu³, Guoping Zhang¹, Jun Wang², Wei Pan², Jiaxin Chen¹, Yali Zhang¹, Jia-Qiang Wu⁴, Dandan Chen², Cheng Chen¹, Siying Peng², Hongliang Yao⁵, Hengming Ke⁶

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: [email protected].
⁶ Department of Biochemistry and Biophysics, The University of North Carolina, 120 Mason Farm Road, Chapel Hill, NC, 27599, USA. Electronic address: [email protected].

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.

MeSH terms

Animals
Cyclic Nucleotide Phosphodiesterases, Type 4* / metabolism
Dose-Response Relationship, Drug
Drug Development
Heterocyclic Compounds / chemical synthesis
Heterocyclic Compounds / chemistry
Heterocyclic Compounds / pharmacology
Humans
Mice
Molecular Docking Simulation
Molecular Structure
Phosphodiesterase 4 Inhibitors* / chemical synthesis
Phosphodiesterase 4 Inhibitors* / chemistry
Phosphodiesterase 4 Inhibitors* / pharmacology
Phosphodiesterase 4 Inhibitors* / therapeutic use
Psoriasis* / drug therapy
RAW 264.7 Cells
Structure-Activity Relationship
Tumor Necrosis Factor-alpha / antagonists & inhibitors
Tumor Necrosis Factor-alpha / metabolism

Substances

Phosphodiesterase 4 Inhibitors
Cyclic Nucleotide Phosphodiesterases, Type 4
Heterocyclic Compounds
Tumor Necrosis Factor-alpha