Discovery of the First-in-Class Intestinal Restricted FXR and FABP1 Dual Modulator ZLY28 for the Treatment of Nonalcoholic Fatty Liver Disease

Abstract

The prevalence of nonalcoholic steatohepatitis (NASH) is increasing rapidly worldwide, and NASH has become a serious problem for human health. Recently, the selective activation of the intestinal farnesoid X receptor (FXR) was considered as a more promising strategy for the treatment of NASH with lesser side effects due to reduced systemic exposure. Moreover, the inhibition of intestinal fatty acid binding protein 1 (FABP1) alleviated obesity and NASH by reducing dietary fatty acid uptake. In this study, the first-in-class intestinal restricted FXR and FABP1 dual-target modulator ZLY28 was discovered by comprehensive multiparameter optimization studies. The reduced systemic exposure of ZLY28 might provide better safety by decreasing the on- and off-target side effects in vivo. In NASH mice, ZLY28 exerted robust anti-NASH effects by inhibiting FABP1 and activating the FXR-FGF15 signaling pathway in the ileum. With the above attractive efficacy and preliminary safety profiles, ZLY28 is worthy of further evaluation as a novel anti-NASH agent.

Tailoring FXR Modulators for Intestinal Specificity: Recent Progress and Insights

“…improvements were then made to compound 89 by constraining the flexibility of the phenylacetic acid. Moving the acetic acid group to the meta position and introducing a cyclopropyl group to the α-position of the acetic acid resulted in similar outcomes to those observed in compound 89, as demonstrated by compound ZLY28 (94) (EC50 (FXR) = 0.143 µM; IC50 (FABP1) = 2.7 µM) (Figure 10) [41]. In in vitro liver microsomal metabolic studies, ZLY28 (94) and 89 exhibited good stability, with over 50% of the original compound remaining after one hour.…”

“…Initially, it was observed that the direct hybrid analog (88) of GW4064 (1) and BMS309403 (87) improved FABP1 inhibition compared to GW4064 (1), indicating that the biphenyl moiety would help induce FABP1 activity. Replacing the phenoxy acetic acid with phenylacetic acid afforded compound 89 (EC 50 (FXR) = 0.135 µM; IC 50 (FABP1) = 2.9 µM) (Figure 10) [41]. This newly developed compound demonstrated enhanced activation of FXR in cell-based assays.…”

“…ZLY28 (94) was discovered while pursuing an FXR-FABP1 dual modulator by improving on the GW4064 (1) scaffold (Figure 10). GW4064 (1) was chosen due to its ability to inhibit FABP1 in comparison to other well-known FXR agonists (EC 50 (FXR) = 0.065 µM; IC 50 (FABP1) = 35.2 µM) [41]. In hopes of mitigating the undesirable properties of GW4064 (1), the questionable stilbene moiety was replaced with a biphenyl (88) as seen in an FABP4 inhibitor BMS309403 (87) (Figure 10) [42].…”

“…Notably, relocating the acetic acid group to the meta position resulted in complete abolition of its activity (i.e., 90). Modifying the substituents on the phenyl ring or the cyclopropyl, derived from the hammerhead structure of compound 1, also led to decreased activity (i.e., 91-92) (Figure 10) [41]. improvements were then made to compound 89 by constraining the flexibility of the phenylacetic acid.…”

Upregulation of Hepatic Glutathione S-Transferase Alpha 1 Ameliorates Metabolic Dysfunction-Associated Steatosis by Degrading Fatty Acid Binding Protein 1

“…FABP1 is highly expressed in hepatocytes and is required for the uptake of FFA [56]. Increasing FABP1 expression in HepG2 cells results in increased uptake of radiolabeled oleic acid by 38% and 78%, respectively [57,58], and downregulation of FABP1 levels has a therapeutic effect in metabolic diseases [48,59]. Here, we have shown that GSTA1 binds directly to FABP1, and higher expression of GSTA1 causes degradation of FABP1, which can alleviate liver diseases.…”