Nidufexor (LMB763), a Novel FXR Modulator for the Treatment of Nonalcoholic Steatohepatitis

J Med Chem. 2020 Apr 23;63(8):3868-3880. doi: 10.1021/acs.jmedchem.9b01621. Epub 2020 Feb 5.


Farnesoid X receptor (FXR) agonists are emerging as important potential therapeutics for the treatment of nonalcoholic steatohepatitis (NASH) patients, as they exert positive effects on multiple aspects of the disease. FXR agonists reduce lipid accumulation in the liver, hepatocellular inflammation, hepatic injury, and fibrosis. While there are currently no approved therapies for NASH, the bile acid-derived FXR agonist obeticholic acid (OCA; 6-ethyl chenodeoxycholic acid) has shown promise in clinical studies. Previously, we described the discovery of tropifexor (LJN452), the most potent non-bile acid FXR agonist currently in clinical investigation. Here, we report the discovery of a novel chemical series of non-bile acid FXR agonists based on a tricyclic dihydrochromenopyrazole core from which emerged nidufexor (LMB763), a compound with partial FXR agonistic activity in vitro and FXR-dependent gene modulation in vivo. Nidufexor has advanced to Phase 2 human clinical trials in patients with NASH and diabetic nephropathy.

MeSH terms

  • Animals
  • Benzothiazoles / chemistry
  • Benzothiazoles / therapeutic use*
  • Chenodeoxycholic Acid / analogs & derivatives*
  • Chenodeoxycholic Acid / chemistry
  • Chenodeoxycholic Acid / therapeutic use
  • Diet, High-Fat / adverse effects*
  • Dogs
  • Humans
  • Isoxazoles / chemistry
  • Isoxazoles / therapeutic use*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Non-alcoholic Fatty Liver Disease / blood
  • Non-alcoholic Fatty Liver Disease / drug therapy*
  • Non-alcoholic Fatty Liver Disease / etiology
  • Protein Structure, Tertiary
  • Rats
  • Receptors, Cytoplasmic and Nuclear / agonists*
  • Treatment Outcome


  • Benzothiazoles
  • Isoxazoles
  • Receptors, Cytoplasmic and Nuclear
  • obeticholic acid
  • farnesoid X-activated receptor
  • Chenodeoxycholic Acid
  • tropifexor