Design, Synthesis, and Pharmacological Evaluation of Dual FXR-LIFR Modulators for the Treatment of Liver Fibrosis

Although multiple approaches have been suggested, treating
mild-to-severe
fibrosis in the context of metabolic dysfunction associated with liver
disease (MASLD) remains a challenging area in drug discovery. Pathogenesis
of liver fibrosis is multifactorial, and pathogenic mechanisms are
deeply intertwined; thus, it is well accepted that future treatment
requires the development of multitarget modulators. Harnessing the
3,4,5-trisubstituted isoxazole scaffold, previously described as a
key moiety in Farnesoid X receptor (FXR) agonism, herein we report
the discovery of a novel class of hybrid molecules endowed with dual
activity toward FXR and the leukemia inhibitory factor receptor (LIFR).
Up to 27 new derivatives were designed and synthesized. The pharmacological
characterization of this series resulted in the identification of 3a as a potent FXR agonist and LIFR antagonist with excellent
ADME properties. In vitro and in vivo characterization identified
compound 3a as the first-in-class hybrid LIFR inhibitor
and FXR agonist that protects against the development of acute liver
fibrosis and inflammation.