ZLY-28

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.