2. Academic Validation
  3. Discovery of 7-alkoxybenzofurans as PDE4 inhibitors with hepatoprotective activity in D-GalN/LPS-induced hepatic sepsis

Discovery of 7-alkoxybenzofurans as PDE4 inhibitors with hepatoprotective activity in D-GalN/LPS-induced hepatic sepsis

  • Eur J Med Chem. 2024 Jun 7:275:116576. doi: 10.1016/j.ejmech.2024.116576.
Chuang Xia 1,  Huizhen Wen 1,  Lei Zheng 1,  Yujie Ni 1,  Huichang Bi 1,  Haitao Wang 1,  Jiangping Xu 2,  Zhong-Zhen Zhou 3
Affiliations

Affiliations

  • 1 Innovation Program of Drug Research on Neurological and Metabolic Diseases, NMPA Key Laboratory for Research and Evaluation of Drug Metabolism & Guangdong Provincial Key Laboratory of New Drug Screening & Guangdong-Hongkong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China.
  • 2 Innovation Program of Drug Research on Neurological and Metabolic Diseases, NMPA Key Laboratory for Research and Evaluation of Drug Metabolism & Guangdong Provincial Key Laboratory of New Drug Screening & Guangdong-Hongkong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China. Electronic address: jpx@smu.edu.cn.
  • 3 Innovation Program of Drug Research on Neurological and Metabolic Diseases, NMPA Key Laboratory for Research and Evaluation of Drug Metabolism & Guangdong Provincial Key Laboratory of New Drug Screening & Guangdong-Hongkong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China. Electronic address: zhouzz@smu.edu.cn.
PMID: 38861808 DOI: 10.1016/j.ejmech.2024.116576
Abstract

Sepsis can quickly result in fatality for critically ill individuals, while liver damage can expedite the progression of sepsis, necessitating the exploration of new strategies for treating hepatic sepsis. PDE4 has been identified as a potential target for the treatment of liver damage. The scaffold hopping of lead compounds FCPR16 and Z19153 led to the discovery of a novel 7-methoxybenzofuran PDE4 Inhibitor 4e, demonstrating better PDE4B (IC50 = 10.0 nM) and PDE4D (IC50 = 15.2 nM) inhibitor activity as a potential anti-hepatic sepsis drug in this study. Compared with FCPR16 and Z19153, 4e displayed improved oral bioavailability (F = 66 %) and longer half-life (t1/2 = 2.0 h) in SD rats, which means it can be more easily administered and has a longer-lasting effect. In the D-GalN/LPS-induced liver injury model, 4e exhibited excellent hepatoprotective activity against hepatic sepsis by decreasing ALT and AST levels and inflammatory infiltrating areas.

Keywords

7-Methoxybenzofurans; D-GalN/LPS-Induced liver injury; Oral bioavailability; PDE4 inhibitors.

Figures
Products