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-activatednuclear receptor.Activation of FXR significantly impacts the expressions of the pivotalgenes involved in bile acid metabolism, inflammation, fibrosis, andhomeostasis of lipid and glucose, leading to considerable interestsin 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 potentfull FXR agonist, shows high selectivity, favorable ADME and pharmacokineticsprofile, along with favorable in vivo activitiesdemonstrated in both rodent PD model and HFD-CCl4 modeland is currently in clinical development in patients with NASH inphase II.