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. In silico and pharmacological characterization of these dual modulators led
to the identification of compound 2o 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.