Design, synthesis, and biological evaluation of FXR/ASK1 dual-target modulators

The dual modulation of FXR and ASK1 is considered a promising therapeutic strategy for metabolic dysfunction-associated fatty liver disease (MAFLD) and its progressive form, metabolic dysfunction-associated steatohepatitis (MASH). GW4064 and GS-4997 are effective regulators for FXR and ASK1, respectively. Through the effective functional group splicing strategy, a new dual-target modulator is designed. Compound Z8 , which acts on both targets, was found to more potently reduce intracellular lipid droplet accumulation in OA-treated HepG2 cells than the FXR agonist GW4064 and the ASK1 inhibitor selonsertib (GS-4997).