Discovery of HPG1860, a Structurally Novel Nonbile Acid FXR Agonist Currently in Clinical Development for the Treatment of Nonalcoholic Steatohepatitis

The farnesoid X receptor (FXR) is a ligand-activated
nuclear receptor.
Activation of FXR significantly impacts the expressions of the pivotal
genes involved in bile acid metabolism, inflammation, fibrosis, and
homeostasis of lipid and glucose, leading to considerable interests
in developing FXR agonists for the treatment of nonalcoholic steatohepatitis
(NASH) or other FXR-relevant diseases. Herein, we describe the design,
optimization, and characterization of a series of N-methylene-piperazinyl derivatives as the nonbile acid FXR agonists.
Particularly, compound 23 (HPG1860), a potent
full FXR agonist, shows high selectivity, favorable ADME and pharmacokinetics
profile, along with favorable in vivo activities
demonstrated in both rodent PD model and HFD-CCl4 model
and is currently in clinical development in patients with NASH in
phase II.