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.
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