Discovery of the First-in-Class Intestinal Restricted FXR and FABP1 Dual Modulator ZLY28 for the Treatment of Nonalcoholic Fatty Liver Disease

• Published in: Journal of medicinal chemistry 2023-05, Vol.66 (9), p.6082-6104
• Main Authors: Ren, Qiang, Chen, Ya, Zhou, Zongtao, Cai, Zongyu, Jiao, Shixuan, Huang, Wanqiu, Wang, Bin, Chen, Siliang, Wang, Wenxin, Cao, Zhijun, Yang, Zhongcheng, Deng, Liming, Hu, Lijun, Zhang, Luyong, Li, Zheng
• Format: Article
• Language: English
• Subjects: Animals; Fatty Acid-Binding Proteins; Humans; Liver - metabolism; Mice; Non-alcoholic Fatty Liver Disease - drug therapy; Non-alcoholic Fatty Liver Disease - metabolism; Obesity; Receptors, Cytoplasmic and Nuclear - metabolism
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.2c01918

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.