Harnessing the Estradienone Scaffold to Develop Dual GPBAR1 and LIFR Modulators for Liver Fibrosis

Fibrosis is a pathological process characterized by excessive deposition of the extracellular matrix (ECM) within tissues. Chronic fibrotic disorders involving the lungs, liver, intestine, and kidneys represent a major cause of morbidity and mortality and remain a major unmet therapeutic need. In the liver, the development of pathological ECM depends on the activation of key cell targets, i.e., the hepatic stellate cells (HSC). HSCs express the leukemia inhibitory factor receptor (LIFR), which promotes fibrosis, and a bile acid-activated receptor, GPBAR1, which attenuates HSC activation. Herein, we report the design and synthesis of a new class of 4,9-estradien-3,17-dione derivatives acting as dual LIFR inhibitors and GPBAR1 agonists. <i>In silico</i> and pharmacological characterization of these dual modulators led to the identification of compound <b>2o</b> as a first-in-class LIFR/GPBAR1 modulator that reverses liver fibrosis in vitro and in vivo. These findings demonstrate the therapeutic potential of LIFR/GPBAR1 hybrid molecules in human fibrotic disorders.