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.
The free fatty acid receptor 1 (FFA1) is a promising anti-diabetic target, and many FFA1 agonists including TAK-875 and AMG-837 are reached in clinical studies. However, the excessive lipophilicity of AMG-837 (ClogP = 6.81) might be a potential downside attributed to the clinical failure of AMG-837. In this study, we introduced the oxime ether moiety to replace the middle benzene of AMG-837 to reduce the lipophilicity. After comprehensive structure-activity relationship study, the optimal compound 7 was identified as a partial agonist with appropriate lipophilicity (EC 50 = 37.6 nM, Efficacy = 71 %, ClogP = 4.73). Moreover, compound 7 exhibited significantly glucose-lowering effects in a dose-dependent manner, and the glucose-lowering effect was equivalent to that of TAK-875 at the dose of 20 mg/kg. In conclusion, this study provided a new series partial agonists bearing oxime ether scaffold, which is worthy for further exploration based on its excellent pharmacological activity and physicochemical property.
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