AI Article Synopsis
- Nonalcoholic steatohepatitis (NASH) is becoming a major global health issue, prompting the search for better treatment strategies.
- A new compound called ZLY28 has been developed, which selectively targets intestinal farnesoid X receptor (FXR) and inhibits fatty acid binding protein 1 (FABP1), potentially leading to fewer side effects.
- In studies with NASH mice, ZLY28 showed strong anti-NASH effects by activating important signaling pathways and is recommended for further research as a promising treatment option.
Article 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.
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| http://dx.doi.org/10.1021/acs.jmedchem.2c01918 | DOI Listing |
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