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

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 log 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 log 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-beta-mediated cardiac fibrosis. Simultaneously, H&E and Masson stains assays of mice liver validated lOg as an excellent anti-hepatofibrosis candidate, which reduced CCI4-induced hepatic fibrosis level prominently. Besides, the molecular binding models identified the essential interactions between 8b and ATX which was coincided with the SARs. (C) 2019 Elsevier Masson SAS. All rights reserved.