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 -methylene-piperazinyl derivatives as the nonbile acid FXR agonists. Particularly, compound (), a potent full FXR agonist, shows high selectivity, favorable ADME and pharmacokinetics profile, along with favorable activities demonstrated in both rodent PD model and HFD-CCl model and is currently in clinical development in patients with NASH in phase II.