2. Academic Validation
  3. Design, Synthesis, and Evaluation of Selective PDE4 Inhibitors for the Therapy of Pulmonary Injury

Design, Synthesis, and Evaluation of Selective PDE4 Inhibitors for the Therapy of Pulmonary Injury

  • J Med Chem. 2025 Feb 13;68(3):3837-3857. doi: 10.1021/acs.jmedchem.4c02969.
Mengjie Li 1,  Gang Li 1,  Yuanhui Liu 1 2,  Jiayu Li 1,  Yanghui Ou 1,  Wen Guan 1,  Zhijun Zeng 1,  Haiyang Tang 3,  Dan Bai 3,  Guoping Zhang 1,  Peiming Huang 1,  Liyan Song 1,  Lianbao Ye 2,  Hengming Ke 4,  Hongliang Yao 1
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 School of Pharmacy, Guangdong Pharmaceutical University, Guangdong 510006, China.
  • 3 State Key Laboratory of Respiratory Disease, Guangzhou Medical University, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510182, China.
  • 4 Department of Biochemistry and Biophysics, The University of North Carolina, 120 Mason Farm Road, Chapel Hill, North Carolina 27599, United States.
PMID: 39847693 DOI: 10.1021/acs.jmedchem.4c02969
Abstract

Pulmonary inflammation is the main cause of lung injury. Phosphodiesterase 4 (PDE4) is a promising anti-inflammatory target for the treatment of respiratory diseases. Herein, we designed and synthesized 43 compounds in two novel series of benzimidazole derivatives as PDE4 inhibitors. Among them, compound A5 showed highly selective inhibition of PDE4, good safety, and liver microsomal stability in vitro. A5 administration remarkably attenuated inflammatory infiltration and pathologic injury of the lung in models of acute lung injury in mice and chronic obstructive pulmonary disease (COPD) in mice. In addition, A5 enhanced sputum secretion, relieved cough in mice, and inhibited phosphorylation of p38 MAP kinase, an important protein in the regulation of lung injury. Overall, A5, as an effective PDE4 Inhibitor without acute toxicity and gastrointestinal reaction, may be a potent candidate for the treatment of pulmonary injury.

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