2. Academic Validation
  3. Discovery of LH10, a novel fexaramine-based FXR agonist for the treatment of liver disease

Discovery of LH10, a novel fexaramine-based FXR agonist for the treatment of liver disease

  • Bioorg Chem. 2024 Feb:143:107071. doi: 10.1016/j.bioorg.2023.107071.
Wanqiu Huang 1,  Zhijun Cao 2,  Wenxin Wang 3,  Zhongcheng Yang 3,  Shixuan Jiao 4,  Ya Chen 3,  Siliang Chen 3,  Luyong Zhang 5,  Zheng Li 6
Affiliations

Affiliations

  • 1 School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, PR China; Key Specialty of Clinical Pharmacy, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, 510006, PR China; Center for Drug Research and Development, Guangdong Pharmaceutical University, Guangzhou 510006, PR China; Key Laboratory of New Drug Discovery and Evaluation of the Guangdong Provincial Education Department, Guangdong Pharmaceutical University, Guangzhou 510006, PR China.
  • 2 School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, PR China; Center for Drug Research and Development, Guangdong Pharmaceutical University, Guangzhou 510006, PR China; Key Laboratory of New Drug Discovery and Evaluation of the Guangdong Provincial Education Department, Guangdong Pharmaceutical University, Guangzhou 510006, PR China.
  • 3 School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, PR China.
  • 4 School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, PR China; Key Specialty of Clinical Pharmacy, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, 510006, PR China; Center for Drug Research and Development, Guangdong Pharmaceutical University, Guangzhou 510006, PR China.
  • 5 School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, PR China; Center for Drug Research and Development, Guangdong Pharmaceutical University, Guangzhou 510006, PR China; Key Laboratory of New Drug Discovery and Evaluation of the Guangdong Provincial Education Department, Guangdong Pharmaceutical University, Guangzhou 510006, PR China; Guangzhou Key Laboratory of Construction and Application of New Drug Screening Model Systems, Guangdong Pharmaceutical University, Guangzhou 510006, PR China. Electronic address: lyzhang@cpu.edu.cn.
  • 6 School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, PR China; Key Specialty of Clinical Pharmacy, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, 510006, PR China; Center for Drug Research and Development, Guangdong Pharmaceutical University, Guangzhou 510006, PR China; Key Laboratory of New Drug Discovery and Evaluation of the Guangdong Provincial Education Department, Guangdong Pharmaceutical University, Guangzhou 510006, PR China; Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Guangzhou, 510006, PR China. Electronic address: lizhengdrug@gdpu.edu.cn.
PMID: 38199141 DOI: 10.1016/j.bioorg.2023.107071
Abstract

Farnesoid X receptor (FXR) was considered as a promising drug target in the treatment of cholestasis, drug-induced liver injury, and non-alcoholic steatohepatitis (NASH). However, the existing FXR agonists have shown different degrees of side effects in clinical trials without clear interpretation. MET-409 in clinical phase Ⅲ, has been proven significantly fewer side effects than that of Other FXR agonists. This may be due to the completely different structure of FEX and Other non-steroidal FXR agonists. Herein, the structure-based drug design was carried out based on FEX, and the more active FXR Agonist LH10 (FEX EC50 = 0,3 μM; LH10 EC50 = 0.14 μM)) was screened out by the comprehensive SAR studies. Furthermore, LH10 exhibited robust hepatoprotective activity on the ANIT-induced cholestatic model and APAP-induced acute liver injury model, which was even better than positive control OCA. In the nonalcoholic steatohepatitis (NASH) model, LH10 significantly improved the pathological characteristics of NASH by regulating several major pathways including lipid metabolism, inflammation, oxidative stress, and fibrosis. With the above attractive results, LH10 is worthy of further evaluation as a novel agent for the treatment of liver disorders.

Keywords

Cholestatic liver disease; DILI; FXR; NAFLD.

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