Design, Synthesis, and Pharmacological Evaluation of Dual FXR-LIFR Modulators for the Treatment of Liver Fibrosis
Pasquale Rapacciuolo, Claudia Finamore, Cristina Di Giorgio, Bianca Fiorillo, Carmen Massa, Ginevra Urbani, Silvia Marchianò, Martina Bordoni, Chiara Cassiano, Elva Morretta, Lucio Spinelli, Antonio Lupia, Federica Moraca, Michele Biagioli, Valentina Sepe, Maria Chiara Monti, Bruno Catalanotti, Stefano Fiorucci, Angela Zampella
Abstract
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.