2. Academic Validation
  3. Design, Synthesis, and Evaluation of Dihydropyrimidine Derivatives as Selective PDE1 Inhibitors for the Treatment of Liver Fibrosis

Design, Synthesis, and Evaluation of Dihydropyrimidine Derivatives as Selective PDE1 Inhibitors for the Treatment of Liver Fibrosis

  • J Med Chem. 2024 Apr 26. doi: 10.1021/acs.jmedchem.4c00461.
Zheng-Jiong Zhao 1 2,  Mei-Yan Jiang 2,  Meng-Xing Huang 1 2,  Yi-Yi Yang 2,  Ling-Ling Feng 2,  Chen Zhang 3,  Yi-You Huang 1,  Hai-Bin Luo 1 4,  Yinuo Wu 2
Affiliations

Affiliations

  • 1 Key Laboratory of Tropical Biological Resources of Ministry of Education and Hainan Engineering Research Center for Drug Screening and Evaluation, School of Pharmaceutical Sciences, Hainan University, Haikou, Hainan 570228, China.
  • 2 State Key Laboratory of Anti-Infective Drug Discovery and Development, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, P. R. China.
  • 3 School of Chemistry and Chemical Engineering, Guangdong Pharmaceutical University, Zhongshan 528458, China.
  • 4 Song Li' Academician Workstation of Hainan University (School of Pharmaceutical Sciences), Yazhou Bay, Sanya 572000, China.
PMID: 38669059 DOI: 10.1021/acs.jmedchem.4c00461
Abstract

Liver fibrosis is a common pathological feature of most chronic liver diseases with no effective drugs available. Phosphodiesterase 1 (PDE1), a subfamily of the PDE super Enzyme, might work as a potent target for liver fibrosis by regulating the concentration of cAMP and cGMP. However, there are few PDE1 selective inhibitors, and none has been investigated for liver fibrosis treatment yet. Herein, compound AG-205/1186117 with the dihydropyrimidine scaffold was selected as the hit by virtual screening. A hit-to-lead structural modification led to a series of dihydropyrimidine derivatives. Lead 13h exhibited the IC50 of 10 nM against PDE1, high selectivity over other PDEs, as well as good safety properties. Administration of 13h exerted significant anti-liver fibrotic effects in bile duct ligation-induced fibrosis rats, which also prevented TGF-β-induced myofibroblast differentiation in vitro, confirming that PDE1 could work as a potential target for liver fibrosis.

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