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

Although multiple approaches have been suggested, treating\nmild-to-severe\nfibrosis in the context of metabolic dysfunction associated with liver\ndisease (MASLD) remains a challenging area in drug discovery. Pathogenesis\nof liver fibrosis is multifactorial, and pathogenic mechanisms are\ndeeply intertwined; thus, it is well accepted that future treatment\nrequires the development of multitarget modulators. Harnessing the\n3,4,5-trisubstituted isoxazole scaffold, previously described as a\nkey moiety in Farnesoid X receptor (FXR) agonism, herein we report\nthe discovery of a novel class of hybrid molecules endowed with dual\nactivity toward FXR and the leukemia inhibitory factor receptor (LIFR).\nUp to 27 new derivatives were designed and synthesized. The pharmacological\ncharacterization of this series resulted in the identification of <b>3a</b> as a potent FXR agonist and LIFR antagonist with excellent\nADME properties. In vitro and in vivo characterization identified\ncompound <b>3a</b> as the first-in-class hybrid LIFR inhibitor\nand FXR agonist that protects against the development of acute liver\nfibrosis and inflammation.