Design, synthesis and anti-NASH effect evaluation of novel GFT505 derivatives in vitro and in vivo.

Non-alcoholic fatty liver disease (NAFLD) is emerging as the largest burden of chronic liver disease worldwide. Nonalcoholic steatohepatitis (NASH) is a progressive form of NAFLD that can progress to cirrhosis and hepatocellular carcinoma. Unfortunately, current treatment options for NASH are very limited. Among the multiple pathways of NASH, peroxisome proliferators-activated receptors (PPARS) are recognized as an important and effective target. GFT 505 is a dual excitement agent for the treatment of PPAR-α/δ for the treatment of NASH. However, its activity and toxicity need to be further improved. Therefore, here we would like to report the design, synthesis and biological evaluation of 11 GFT 505 derivatives. The initial cytotoxicity through proliferation activity of HepG2 cells and in vitro anti-NASH activity evaluation demonstrated that under the same concentration, the compound 3d possess significantly lower cytotoxicity and better anti-NASH activity than that of GFT 505. Moreover, Molecular docking also shows that 3d and PPAR-α/δ can form a stable hydrogen bond and have the lowest binding energy. Therefore this novel molecule 3d was selected to go further in vivo investigation. Methionine-choline deficiency (MCD) induced C57BL/6J NASH model mice was used for the in vivo biological experiments and the compound 3d demostrated lower liver toxicity than that of GFT 505 in the body at the same dose, and it did more effectively improve hyperlipidemia, liver fat degeneration and liver inflammation as well as significantly enhance the content of the GSH which is inportant for the liver protection. This study suggested that the compound 3d is a very promising lead compound for the treatment of NASH.