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

Abstract

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.

Tailoring FXR Modulators for Intestinal Specificity: Recent Progress and Insights

“…F6 (19) was developed as a potent intestine-selective FXR antagonist for the treatment of NASH [28]. Betulinic acid (12) was chosen as the starting point for developing 19 since it had previously been reported as an FXR agonist (Figure 4) [29]. In order to further mimic bile acids, the hydroxyl group at the C 3 position was inverted to the α position and converted to an ester, leading to XYT458B (13) (IC 50 = 7.9 µM) (Figure 4).…”

“…GW4064 (1) is the first non-bile acid FXR agonist and has remained the main template for most non-steroidal agonists since its discovery (Figure 2). Although GW4064 (1) is UV sensitive and potentially toxic, several derivatives of GW4064 (1) have made it to clinical trials such as Tropifexor (2), Cilofexor (3), and Tern-101 (4) (Figure 2) [12]. Although these compounds show promise in treating NASH, their advancement has been hindered by the presence of unwanted side effects like pruritus and dyslipidemia.…”

“…Molecules 2024, 29, x FOR PEER REVIEW 3 of 30 (Figure 2) [12]. Although these compounds show promise in treating NASH, their advancement has been hindered by the presence of unwanted side effects like pruritus and dyslipidemia.…”

Farnesoid X receptor: From Structure to Function and Its Pharmacology in Liver Fibrosis

“…However, combining cilofexor with firsocostat effectively alleviated steatosis and inflammation and lowered ALT, AST, and TBIL, thus improving the fibrosis score (≤F2) [ 223 ]. The latest study revealed that the FXR agonist HPG1860 displayed promising antifibrotic effects in clinical treatment for NASH, with reduced pruritus, and the notable finding was that there was no significant elevation of LDL-C within 16 weeks [ 224 ]. Other FXR regulators undergoing clinical trials, as listed on ClinicalTrials.gov ( https://clinicaltrials.gov/ ), are outlined in Table 2 .…”