Optimization and evaluation of novel tetrahydropyrido[4,3-d]pyrimidine derivatives as ATX inhibitors for cardiac and hepatic fibrosis.

Abstract

Aiming to develop potent autotaxin (ATX) inhibitors for fibrosis diseases, a novel series of tetrahydropyrido[4,3-d]pyrimidine derivatives was designed and synthesized based on our previous study. The enzymatic assay combined with anti-proliferative activities against cardiac fibroblasts (CFs) and hepatic stellate cell (HSC) in vitro were applied for preliminary evaluation of anti-fibrosis potency of target compounds, resulting in two outstanding ATX inhibitors 8b and 10g with the IC50 values in a nanomolar range (24.6 and 15.3 nM). Differently, 8b was the most prominent compound against CFs with inhibition ratio of 81.5%, while 10g exhibited the maximum inhibition ratio of 83.7% against t-HSC/Cl-6 cells. In the further pharmacological evaluations in vivo, collagen deposition assay demonstrated the conspicuous capacity of 8b to suppress TGF-β-mediated cardiac fibrosis. Simultaneously, H&E and Masson stains assays of mice liver validated 10g as an excellent anti-hepatofibrosis candidate, which reduced CCl4-induced hepatic fibrosis level prominently. Besides, the molecular binding models identified the essential interactions between 8b and ATX which was coincided with the SARs.

• Authors: Nan Jiang, Yuhong Zhou, Minglin Zhu, Junlong Zhang, Meng Cao, Hongrui Lei, Ming Guo, Ping Gong, Guangyue Su, Xin Zhai
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 187 Pg. 111904 (Feb 01 2020) ISSN: 1768-3254 [Electronic] France
• PMID: 31806537 (Publication Type: Journal Article)
• Copyright: Copyright © 2019 Elsevier Masson SAS. All rights reserved.

Chemical References

• Enzyme Inhibitors
• Pyridines
• Pyrimidines
• tetrahydropyrido(4,3-d)pyrimidine
• Phosphoric Diester Hydrolases
• alkylglycerophosphoethanolamine phosphodiesterase

Topics

• Animals
• Cell Line
• Dose-Response Relationship, Drug
• Enzyme Inhibitors (chemical synthesis, chemistry, pharmacology)
• Fibroblasts (drug effects, metabolism)
• Fibrosis (drug therapy, metabolism, pathology)
• Humans
• Male
• Mice
• Mice, Inbred Strains
• Molecular Docking Simulation
• Molecular Structure
• Phosphoric Diester Hydrolases (metabolism)
• Pyridines (chemical synthesis, chemistry, pharmacology)
• Pyrimidines (chemical synthesis, chemistry, pharmacology)
• Structure-Activity Relationship