Nonalcoholic fatty liver disease (NAFLD), characterized by excessive accumulation of fat in hepatocytes, is a common chronic liver disease including a wide spectrum of disorders ranging from nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH) and cirrhosis. However, 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 a more promising strategy for the treatment of NASH. Moreover, FXR shows 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. Hence, we will introduce a first-in-class FXR/FABP1 dual modulator-ZLY28.

ZLY28 is an orally active FXR/FABP1 dual modulator.

In vitro experiments, ZLY28 exhibits an EC₅₀ value of 143 nM for FXR, and shows an IC₅₀ value of 2.7 μM for FABP1. In addition, ZLY28 shows suitable stability of liver microsomes and high target selectivity.

Besides, in NASH mice, ZLY28 exerted robust anti-NASH effects by inhibiting FABP1 and activating the FXR-FGF15 signaling pathway in the ileum. Moreover, when in vivo experiments, ZLY28 (20 mg/kg; p.o.; single) significantly alleviates fatty liver by regulating multiple pathogeneses. Such as lipid metabolism, inflammation, oxidative stress, and fibrosis in the NASH mice model. Moreover, ZLY28 significantly increased the enzyme activities of SOD and GSH-Px in NASH mice.

In addition, ZLY28 might provide better safety by decreasing the on- and off-target side effects in vivo.

Taken together, ZLY28 exhibited an acceptable safety profile with no acute toxicity to major organs and a wide therapeutic window suitable for further research. All in all, ZLY28 is a promising FXR and FABP1 dual modulator for the research of NASH.

Reference:

[1] Ren Q, et al. J Med Chem. 2023 May 11;66(9):6082-6104.