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

  • J Med Chem. 2023 May 11;66(9):6082-6104. doi: 10.1021/acs.jmedchem.2c01918.
Qiang Ren  1  2 ,  Ya Chen  1 ,  Zongtao Zhou  1  3  2  4 ,  Zongyu Cai  1 ,  Shixuan Jiao  1  2 ,  Wanqiu Huang  1  2 ,  Bin Wang  1 ,  Siliang Chen  1 ,  Wenxin Wang  1  2 ,  Zhijun Cao  1  2 ,  Zhongcheng Yang  1 ,  Liming Deng  1  2 ,  Lijun Hu  1 ,  Luyong Zhang  1  2  4  5 ,  Zheng Li  1  3  2
Affiliations
  • 1. School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, PR China.
  • 2. Key Laboratory of New Drug Discovery and Evaluation of the Guangdong Provincial Education Department, Guangdong Pharmaceutical University, Guangzhou 510006, PR China.
  • 3. Key Specialty of Clinical Pharmacy, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou 510006, PR China.
  • 4. Guangzhou Key Laboratory of Construction and Application of New Drug Screening Model Systems, Guangdong Pharmaceutical University, Guangzhou 510006, PR China.
  • 5. Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing 210009, PR China.
PMID: 37079895 DOI: 10.1021/acs.jmedchem.2c01918
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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